Fracture liaison service model: project design and accreditation.

Frailty fractures place a significant socioeconomic burden on the health care system. The Italian Society of Orthopaedics and Traumatology (SIOT) is proceeding to fracture liaison service (FLS) model accreditation in several Italian Fracture Units (FUs), which provides a multidisciplinary approach for the management of the fragility fracture patient. INTRODUCTION: Osteoporosis and the resulting fragility fractures, particularly femoral fractures, place significant socioeconomic burdens on the health care system globally. In addition, there is a general lack of awareness of osteoporosis, resulting in underestimation of the associated risks and suboptimal treatment of the disease. The fracture liaison service (FLS) represents an exemplary model of post-fracture care that involves a multidisciplinary approach to the frail patient through the collaboration of multiple specialists. The purpose of this article is to highlight the path undertaken by the Italian Society of Orthopaedics and Traumatology (SIOT) for the purpose of certification of numerous FLS centers throughout Italy. METHODS: SIOT is proceeding with international FLS accreditation in several Italian Fracture Units (FUs), following the creation of a model that provides specific operational and procedural steps for the management of fragility fractures throughout the country. FUs that decide to join the project and implement this model within their facility are then audited by an ACCREDIA-accredited medical certification body. RESULTS: The drafted FLS model, thanks to the active involvement of a panel of experts appointed by SIOT, outlines a reference operational model that describes a fluid and articulated process that identifies the procedure of identification, description of diagnostic framing, and subsequent initiation of appropriate secondary prevention programs for fractures of individuals who have presented with a recent fragility fracture of the femur. CONCLUSION: Accreditation of this prevention model will enable many facilities to take advantage of this dedicated diagnostic-therapeutic pathway for the purpose of fracture prevention and reduction of associated health and social costs.

Life-history traits of the leatherjacket Meuschenia scaber, a long-lived monacanthid.

The present study describes the age and growth of the leatherjacket Meuschenia scaber, a common Australasian monacanthid and valued by-catch of the inshore bottom trawl fishery in New Zealand. Age was determined from the sagittal otoliths of 651 individuals collected between July 2014 and March 2016 in the Hauraki Gulf of New Zealand. Otolith sections revealed alternating opaque and translucent zones and edge-type analysis demonstrated that these are deposited annually. Meuschenia scaber displayed rapid initial growth, with both males and females reaching maturity in 1-2 years and 50% of both sexes matured at 1·5 years. Maximum age differed substantially between the sexes, at 9·8 years for males and 17·1 years for females. Growth rate was similar between sexes, although males reached greater mass at age than females in the early part of the lifespan. The length-mass relationship differed significantly between the sexes, with males displaying negative allometric growth and females isometric growth. Female condition was highest in July, declined in August with the onset of spawning and showed a slight peak in January and February, immediately following the spawning season. This study substantially extends the maximum longevity recorded for monacanthids, although males had much shorter lifespans and higher mortality, than females.

Plasma heavy metal levels correlate with deregulated gene expression of detoxifying enzymes in osteoporotic patients.

Heavy metal levels appear to be associated with low bone mineral density (BMD) and the consequent osteoporosis risk, but the relationship with the disease has not been clearly defined. The altered expression pattern of numerous genes, including detoxifying genes, seems to play a pivotal role in this context, leading to increased susceptibility to several diseases, including osteoporosis. The purpose of this study is to analyse circulating heavy metals levels and the expression of detoxifying genes in osteoporotic patients (OPs, n = 31), compared with healthy subjects (CTRs, n = 32). Heavy metals concentration in plasma samples was determined by Inductively Coupled Plasma Mass Spectrometry (ICP-MS), and the subsequent expression analysis of NAD(P)H quinone dehydrogenase 1 (NQO1), Catalase (CAT), and Metallothionein 1E (MT1E) genes in Peripheral Blood Mononuclear Cells (PBMCs) was assessed by real-time polymerase chain reaction (qRT-PCR). Copper (Cu), mercury (Hg), molybdenum (Mo) and lead (Pb) were found to be significantly higher in the plasma of OPs compared to CTRs. Analysis of the expression levels of detoxifying genes showed a significant decrease in CAT and MT1E in OP group. In addition, Cu correlated positively with the expression levels of both CAT and MT1E in CTRs group and MT1E in OPs. This study shows an increased circulating concentration of certain metals combined with an altered expression pattern of detoxifying genes in OPs, highlighting a novel aspect to be investigated in order to better characterize the role of metals in the pathogenesis of osteoporosis.

Comparison of N-(4-hydroxyphenyl)retinamide and all-trans-retinoic acid in the regulation of retinoid receptor-mediated gene expression in human breast cancer cell lines.

The activities of N-(4-hydroxyphenyl)retinamide [(4-HPR), Fenretinide] and all-trans-retinoic acid (RA) were determined for (a) the inhibition of cell proliferation; (b) the activation of human retinoid receptor-mediated target gene expression; (c) the inhibition of estradiol- and progesterone-induced gene activation in breast cancer cell lines; and (d) the regulation of the expression of tumor suppressor retinoblastoma protein. Similar to RA, both 4-HPR and its active metabolite N-(4-methoxyphenyl)retinamide (4-MPR) effectively impeded the growth of MCF7 and T-47D human breast cancer cell lines, except that 4-HPR also inhibited the proliferation of RA-resistant BT-20 cells. However, when tested in human recombinant retinoic acid receptor (RAR-alpha, RAR-beta, and RAR-gamma)-induced reporter gene assays, RA was much more potent (>100-fold) than either 4-HPR or 4-MPR. 4-HPR induced transcriptional activation through all three RAR subtypes at 1-10microM, while RA showed comparable activity at 10-100microM. Despite the apparent weak interaction at the RAR level, 4-HPR was comparable to RA in the inhibition of both estrogen receptor- and progesterone receptor-mediated transcriptional activation in MCF7 and T-47D cells, respectively. Moreover, similar to RA, 4-HPR and 4-MPR caused marked up-regulation of tumor suppressor retinoblastoma protein in both MCF7 and T-47D cells. Since RA and 4-HPR showed comparable activity in the inhibition of estrogen recptor- and progesterone receptor-induced gene transcription and in the stimulation of retinoblastoma protein expression in MCF7 and T-47D cells, the reduced RAR activation by 4-HPR may result in the lack of hepatic toxicity and therefore the improved therapeutic efficacy relative to RA.

Differential regulation of human progesterone receptor A and B form-mediated trans-activation by phosphorylation.

Hormone-dependent phosphorylation of progesterone receptors (PRs) plays a functional role in their transcriptional activity. However, hormone-independent phosphorylation has also been shown to modulate the chicken PR-mediated trans-activation in the presence of phosphorylating agents. The present study was designed to investigate the effects of protein kinase A- and protein kinase C-mediated signal transduction pathways on the regulation of the activity of the two forms of human PR (hPRA and hPRB). Similar to chicken PR, hPR was activated by 8-bromo-cAMP (8-Br-cAMP) in the absence of ligand, whereas 8-Br-cAMP synergized with the progestin agonist R5020 to amplify hPRA- and hPRB-mediated reporter activity. Interestingly, the effect of 8-Br-cAMP was much more pronounced on hPRA-induced trans-activation than on hPRB. This differential regulation by 8-Br-cAMP could also be mimicked by okadaic acid. Both mouse mammary tumor virus-thymidine kinase-chloramphenicol acetyl transferase and progesterone response element-thymidine kinase-chloramphenicol acetyl transferase showed a similar response to 8-Br-cAMP in the presence of R5020. Protein kinase C, on the other hand, did not discriminate between hPRA- and hPRB-mediated trans-activation. Unlike 8-Br-cAMP, phorbol 12-myristate 13-acetate did not cause marked ligand-independent trans-activation through either of the two receptor forms. RU486, an antagonist of progestin, preferentially blocked R5020-induced trans-activation compared to R5020 + 8-Br-cAMP synergism. As expected, H-89, a specific inhibitor of protein kinase A was more effective in inhibiting ligand-independent activity. Western analysis of transfected receptors suggested that 8-Br-cAMP and 8-Br-cAMP + R5020 but not R5020 alone down-regulated the level of hPRB in COS-1 cells. Only marginal modulation of hPRA levels was observed with R5020 treatment in the presence and absence of 8-Br-cAMP. These data suggest that R5020 and 8-Br-cAMP mediate PR-dependent transactivation through distinct pathways, and that phosphorylation can differentially regulate the activity of hPRA and hPRB forms, an observation which may be important for selective target gene activation in vivo by progestins.

First search for gravitational wave bursts with a network of detectors

We report the initial results from a search for bursts of gravitational radiation by a network of five cryogenic resonant detectors during 1997 and 1998. This is the first significant search with more than two detectors observing simultaneously. No gravitational wave burst was detected. The false alarm rate was lower than 1 per 10(4) yr when three or more detectors were operating simultaneously. The typical threshold was H approximately 4x10(-21) Hz-1 on the Fourier component at approximately 10(3) Hz of the gravitational wave strain amplitude. New upper limits for amplitude and rate of gravitational wave bursts have been set.

Ex vivo spermine dialdehyde treatment prevents lethal GVHD in a murine bone marrow transplantation model.

Spermine dialdehyde (SDA), an oxidized product of spermine which irreversibly suppresses T cell and NK cell activities, was evaluated as an ex vivo purging agent in the prevention of graft-versus-host disease (GVHD) in mice transplanted with SDA-treated allogeneic bone marrow. In this model, lethally irradiated C3H (H-2k) mice received BALB/c (H-2d) bone marrow and spleen cell mixtures which had been treated ex vivo for 10 min with SDA. Mice receiving SDA-treated cells survived past 100 days whereas mice in the control group died between days 25-35 suffering from severe GVHD. Surviving mice from the SDA-treated groups exhibited full chimerism at day 120. In vitro assays indicated that SDA inhibited T cell and NK cell activities at concentrations that spared myeloid cell growth. When a minimum number of bone marrow cells were used for reconstitution, SDA-treated marrow reconstituted lethally irradiated mice as effectively as control marrow suggesting that SDA had little impact on early myeloid cells which are required for engraftment. SDA may have clinical application as a purging agent in allogeneic bone marrow transplantation.

Past, present and future strategies of immunotherapy in gynecological malignancies.

Recently, the combining of different drugs has greatly improved response and survival rates in gynecological malignancies. Results are however far from being satisfactory. Treatments used in case of advanced or recurrent disease offer limited results in terms of long-term responses. The urgent need for new and more effective treatments has prompted researchers to investigate and propose new therapeutic strategies. One of the most interesting approaches that are being explored is constituted by immunotherapy. Currently, immunotherapeutic strategies include vaccination with peptide, viral vectors, carbohydrates and antiidiotypic antibodies. In addition, cell based immunotherapy has been adopted in vitro activated lymphocytes and dendritic cells. Most experience has been acquired in ovarian cancer and cervical cancer. Little has been investigated in endometrial and rare gynecologic neoplasms.The clinical experiences and results achieved with immunotherapy in this setting of patients have been reviewed and the future avenues that are currently being explored have also been discussed.

Massive rotator cuff tear treated with a synthetic patch: a case report 16 years after surgery.

Massive rotator cuff tears usually cannot be repaired due to tendon atrophy and marked retraction, as well as muscles fatty degeneration. There are several options for surgical treatment: open or arthroscopic debridement with or without subacromial decompression, arthroscopic isolated biceps tenotomy, partial tendon repair, use of synthetic or biologic patches, tendon transfers, hemiarthroplasty, reverse arthroplasty, and arthrodesis. In this article, we will discuss a particular case of massive rotator cuff tear treated with Marlex mesh. The patient was clinically, radiologically, and MRI checked 16 years after the surgical implant. The active function of shoulder had preserved very well, the Constant score was 76. The X-rays showed a limited progression of osteoarthritis without further cranial migration of the humeral head. At MR cartilage preservation was appreciated, the patch being in good position and the teres minor being smaller than average but it was nonetheless present. This case report can highlight the usefulness of patches in patients with irreparable rotator cuff lesion both for the immediate benefit in terms of pain, strength, movement, and in perspective allowing for the preservation of anatomical structures that might avoid the need for a prosthetic implant over the years.

Immunology of gynecologic neoplasms: analysis of the prognostic significance of the immune status.

Gynecologic Oncology has changed in the last few decades. An increasing proportion of patients is benefiting from long term survival although patients diagnosed with advanced disease suffer from a poor prognosis. Unfortunately, several recent studies are confirming that changing the combinations of "traditional" cytotoxic drugs is unlikely to obtain a real breakthrough in survival rates. Furthermore, there is discouraging data regarding consolidation therapies. It is, therefore, necessary to identify new target therapies with a minimal impact on quality of life. It is likely that new breakthroughs are only going to be achieved when changes in therapies are tailored to the entire natural history of the disease and on specific patient characteristic's. Since the discovery that tumor infiltrating lymphocytes represent an independent prognostic factor in ovarian cancer patients, several researchers have dedicated their attention to cancer immune response in order to identify prognostic factors and immunological targets. Analyses on immunophenotype at diagnosis and throughout the entire course of treatment are currently ongoing and are giving the new diagnostic, prognostic and therapeutic tools to the physicians. Furthermore new antigens and new vaccination strategies are being investigated. Encouraging data on selected patient populations have been observed recently. The objective of the present review is to define the immunology of women affected by gynecological malignancies and describe new immunological targets for prognostic and therapeutic use.

Suppression of NF kappa B activation and NF kappa B-dependent gene expression by tepoxalin, a dual inhibitor of cyclooxygenase and 5-lipoxygenase.

Tepoxalin, a dual inhibitor of cyclooxygenase (CO) and 5-lipoxygenase (5LO) with cytokine modifying activity, is also a potent inhibitor of the transcription factor, nuclear factor kappa B (NF kappa B). NF kappa B is a pleiotropic activator that is involved in the regulation of many genes whose products participate in immune or inflammatory responses. Tepoxalin inhibited in a dose related manner NF kappa B activation by PMA + ionomycin or H2O2 in Jurkat and HeLa cells. TNF-alpha-induced NF kappa B was also inhibited by tepoxalin in HeLa cells, while relatively less marked inhibition was observed in Jurkat cells. Activation of NF kappa B in several monocytic cell lines was also suppressed by tepoxalin. However AP-1 stimulation under the same conditions was not affected by tepoxalin. Other CO, LO inhibitors such as naproxen or zileuton did not inhibit NF kappa B activities. This inhibitory activity of tepoxalin was further illustrated by its suppression of NF kappa B regulated genes such as IL-6 in PMA stimulated human PBL and c-myc in IL-2 dependent T cell lines. Tepoxalin also blocked PMA + ionomycin-induced I kappa B degradation in a time-dependent fashion. The possible mechanism of tepoxalin in NF kappa B activation and its potential clinical application are discussed.

Purification, characterization, and structural elucidation of the active moiety of the previously called "suppressor activating factor (SAF)".

Upon extensive purification of the serum-free supernatant produced by a mutant T cell line (6T-CEM), an immunosuppressive activity was found to reside in an oxidized product of spermine, spermine dialdehyde (SDA). The activity was purified to homogeneity from a serum-free supernatant by using gel filtration chromatography and reverse-phase C18 HPLC. Fast Atom Bombardment (FAB) mass spectral analysis revealed its MW to be 202 and Electron Impact (EI) analysis of the acetylated material identified the purified molecule to be spermine. In the presence of human or rodent plasma, spermine exhibited no immunosuppressive activity up to 2 mg/ml. However, when assayed in the presence of FCS, which contains polyamine oxidase (PAO), spermine is oxidized to its corresponding dialdehyde which is active at 0.1 microM/ml. We have previously described a high molecular weight suppressor activating factor (SAF) found in the serum-containing supernatant of the 6T-CEM cell line. Our preliminary biological data suggest that SDA is probably responsible for the immunosuppressive activities previously observed for the SAF. The strong affinity of SDA for proteins and thiocompounds may account for the apparent high MW previously reported for SAF.

Mechanism of action of a suppressor-activating factor (SAF) produced by a human T cell line.

We previously described a potent suppressor-activating factor (SAF) produced constitutively by a 6-thioguanine-resistant mutant of the human T cell line CEM. In the present study, we investigated the mechanism of action of SAF. After a brief (4- to 18-hr) exposure to SAF at 37 degrees C, T lymphocytes (either unseparated, or purified OKT4+ and OKT8+ subpopulations), but not B lymphocytes, suppressed allogeneic and syngeneic T cells in co-culture experiments, apparently via the release of a suppressor activity. The total T cell-released suppressor activity (TRSA) accumulated after 3 days culture post-treatment was about 100- to 500-fold higher than the original suppressor activity (SAF) added to trigger the release. Arresting protein or DNA synthesis, or even killing the cells did not affect the release of TRSA by T lymphocytes, but lowering the incubation temperature to 4 degrees C reduced it drastically. Pre-treatment of T lymphocytes with the metabolic inhibitor, sodium azide, or the adenylate cyclase stimulator, prostaglandin E2, or the addition of exogenous dibutyryl cAMP, all suppressed the release of TRSA. The presence of monoclonal antibody OKT3, but not OKT4 or OKT8, enhanced the release of TRSA. The presence of OKT11 blocked the release of SAF. The functional characteristics of TRSA appeared to be identical to those of SAF. However, unlike SAF, interaction of T lymphocytes with TRSA triggered only marginal enhancement of suppressor activity. In addition, the kinetics of the suppression mediated by SAF showed a much larger increment as a function of time than that mediated by TRSA. Taken together, the data suggest that SAF might represent an activated form of SAF, and that the continuous activation of SAF by lymphocytes in culture may account for its high potency in suppressing T cell proliferation in vitro.