30-day in-hospital mortality after acute myocardial infarction in Tuscany (Italy): An observational study using hospital discharge data

Abstract Background: Coronary heart disease is the leading cause of mortality in the world. One of the outcome indicators recently used to measure hospital performance is 30-day mortality after acute myocardial infarction (AMI). This indicator has proven to be a valid and reproducible indicator of the appropriateness and effectiveness of the diagnostic and therapeutic process for AMI patients after hospital admission. The aim of this study was to examine the determinants of inter-hospital variability on 30-day in-hospital mortality after AMI in Tuscany. This indicator is a proxy of 30-day mortality that includes only deaths occurred during the index or subsequent hospitalizations. Methods: The study population was identified from hospital discharge records (HDRs) and included all patients with primary or secondary ICD-9-CM codes of AMI (ICD-9 codes 410.xx) that were discharged between January 1, 2009 and November 30, 2009 from any hospital in Tuscany. The outcome of interest was 30-day all-cause in-hospital mortality, defined as a death occurring for any reason in the hospital within 30 days of the admission date. Because of the hierarchical structure of the data, with patients clustered into hospitals, random-effects (multilevel) logistic regression models were used. The models included patient risk factors and random intercepts for each hospital. Results: The study included 5,832 patients, 61.90% male, with a mean age of 72.38 years. During the study period, 7.99% of patients died within 30 days of admission. The 30-day in-hospital mortality rate was significantly higher among patients with ST segment elevation myocardial infarction (STEMI) compared with those with non-ST segment elevation myocardial infarction (NSTEMI). The multilevel analysis which included only the hospital variance showed a significant inter-hospital variation in 30-day in-hospital mortality. When patient characteristics were added to the model, the hospital variance decreased. The multilevel analysis was then carried out separately in the two strata of patients with STEMI and NSTEMI. In the STEMI group, after adjusting for patient characteristics, some residual inter-hospital variation was found, and was related to the presence of a cardiac catheterisation laboratory. Conclusion: We have shown that it is possible to use routinely collected administrative data to predict mortality risk and to highlight inter-hospital differences. The distinction between STEMI and NSTEMI proved to be useful to detect organisational characteristics, which affected only the STEMI subgroup. Keywords: Myocardial infarction, Mortality, Cardiovascular risk, Medical record

Calcium Binds to Transthyretin with Low Affinity

The plasma protein transthyretin (TTR), a transporter for thyroid hormones and retinol in plasma and cerebrospinal fluid, is responsible for the second most common type of systemic (ATTR) amyloidosis either in its wild type form or as a result of destabilizing genetic mutations that increase its aggregation propensity. The association between free calcium ions (Ca2+) and TTR is still debated, although recent work seems to suggest that calcium induces structural destabilization of TTR and promotes its aggregation at non-physiological low pH in vitro. We apply high-resolution NMR spectroscopy to investigate calcium binding to TTR showing the formation of labile interactions, which leave the native structure of TTR substantially unaltered. The effect of calcium binding on TTR-enhanced aggregation is also assessed at physiological pH through the mechano-enzymatic mechanism. Our results indicate that, even if the binding is weak, about 7% of TTR is likely to be Ca2+-bound in vivo and therefore more aggregation prone as we have shown that this interaction is able to increase the protein susceptibility to the proteolytic cleavage that leads to aggregation at physiological pH. These events, even if involving a minority of circulating TTR, may be relevant for ATTR, a pathology that takes several decades to develop

Migrant pathways to community mental health centres in Italy.

Background: Many studies indicate that migrants in western countries have limited access to and low utilization of community mental health centres (CMHCs) despite the high prevalence of mental disorders. Aims: We aimed to compare migrant pathways to care across four CMHCs located in different Italian provinces and to identify pathway to care predictors. Methods: Migrants attending the four CMHCs between 1 July 1999 and 31 December 2007 were included in the study. Data were gathered retrospectively from clinical data sets and chart review. Results: Five hundred and eleven (511) migrants attended the four CMHCs, 61% were referred by GPs or other health services and 39% followed non-medical pathways to care (self-referral or through social and voluntary organizations), with important site variations. Younger age and being married were predictors of medical pathways to care; lacking a residence permit and having a diagnosis of substance abuse were related to non-medical pathways. Conclusions: Pathways to CMHCs are complex and influenced by many factors. Non-medical pathways to care seem to be frequent among migrants in Italy. More attention should be paid to developing psychiatric consultation liaison models that also encompass the social services and voluntary organizations

IBtkα Activates the β‐Catenin‐Dependent Transcription of MYC through Ubiquitylation and Proteasomal Degradation of GSK3βin Cancerous B Cells

The IBTK gene encodes the IBtkα protein that is a substrate receptor of E3 ubiquitin ligase, Cullin 3. We have previously reported the pro‐tumorigenic activity of Ibtk in MYC‐dependent B‐ lymphomagenesis observed in Eμ‐myc transgenic mice. Here, we provide mechanistic evidence of the functional interplay between IBtkα and MYC. We show that IBtkα, albeit indirectly, activates the β‐catenin‐dependent transcription of the MYC gene. Of course, IBtkαassociates with GSK3β and promotes its ubiquitylation, which is associated with proteasomal degradation. This event increases the protein level of β‐catenin, a substrate of GSK3β, and results in the transcriptional activation of the MYC and CCND1 target genes of β‐catenin, which are involved in the control of cell division and apoptosis. In particular, we found that in Burkitt’s lymphoma cells, IBtkα silencing triggered the downregulation of both MYC mRNA and protein expression, as well as a strong decrease of cell survival, mainly through the induction of apoptotic events, as assessed by using flow cytometry‐based cell cycle and apoptosis analysis. Collectively, our results shed further light on the complex puzzle of IBtkα interactome and highlight IBtkα as a potential novel therapeutic target to be employed in the strategy for personalized therapy of B cell lymphoma

Migrant pathways to community mental health centres in Italy.

Background: Many studies indicate that migrants in western countries have limited access to and low utilization of community mental health centres (CMHCs) despite the high prevalence of mental disorders. Aims: We aimed to compare migrant pathways to care across four CMHCs located in different Italian provinces and to identify pathway to care predictors. Methods: Migrants attending the four CMHCs between 1 July 1999 and 31 December 2007 were included in the study. Data were gathered retrospectively from clinical data sets and chart review. Results: Five hundred and eleven (511) migrants attended the four CMHCs, 61% were referred by GPs or other health services and 39% followed non-medical pathways to care (self-referral or through social and voluntary organizations), with important site variations. Younger age and being married were predictors of medical pathways to care; lacking a residence permit and having a diagnosis of substance abuse were related to non-medical pathways. Conclusions: Pathways to CMHCs are complex and influenced by many factors. Non-medical pathways to care seem to be frequent among migrants in Italy. More attention should be paid to developing psychiatric consultation liaison models that also encompass the social services and voluntary organizations

Human wild-type and D76N β_{2}-microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegans

β2-microglobulin (β2-m) is a plasma protein derived from physiological shedding of the class I major histocompatibility complex (MHCI), causing human systemic amyloidosis either due to persistently high concentrations of the wild-type (WT) protein in hemodialyzed patients, or in presence of mutations, such as D76N β2-m, which favor protein deposition in the adulthood, despite normal plasma levels. Here we describe a new transgenic Caenorhabditis elegans (C. elegans) strain expressing human WT β2-m at high concentrations, mimicking the condition that underlies dialysis-related amyloidosis (DRA) and we compare it to a previously established strain expressing the highly amyloidogenic D76N β2-m at lower concentrations. Both strains exhibit behavioral defects, the severity of which correlates with β2-m levels rather than with the presence of mutations, being more pronounced in WT β2-m worms. β2-m expression also has a deep impact on the nematodes' proteomic and metabolic profiles. Most significantly affected processes include protein degradation and stress response, amino acids metabolism, and bioenergetics. Molecular alterations are more pronounced in worms expressing WT β2-m at high concentration compared to D76N β2-m worms. Altogether, these data show that β2-m is a proteotoxic protein in vivo also in its wild-type form, and that concentration plays a key role in modulating pathogenicity. Our transgenic nematodes recapitulate the distinctive features subtending DRA compared to hereditary β2-m amyloidosis (high levels of non-mutated β2-m vs. normal levels of variant β2-m) and provide important clues on the molecular bases of these human diseases

Monitoring multiple myeloma by idiotype-specific peptide binders of tumor-derived exosomes.

Abstract Tumor-derived exosomes (TDEs) play a pivotal role in tumor establishment and progression, and are emerging biomarkers for tumor diagnosis in personalized medicine. To date, there is a lack of efficient technology platforms for exosome isolation and characterization. Multiple myeloma (MM) is an incurable B-cell malignancy due to the rapid development of drug-resistance. MM-released exosomes express the immunoglobulin B-cell receptor (Ig-BCR) of the tumor B-cells, which can be targeted by Idiotype-binding peptides (Id-peptides). In this study, we analyzed the production of MM-released exosomes in the murine 5T33MM multiple myeloma model as biomarkers of tumor growth. To this end, we selected Id-peptides by screening a phage display library using as bait the Ig-BCR expressed by 5T33MM cells. By FACS, the FITC-conjugated Id-peptides detected the MM-released exosomes in the serum of 5T33MM-engrafted mice, levels of which are correlated with tumor progression at an earlier time point compared to serum paraprotein. These results indicate that Id-peptide-based recognition of MM-released exosomes may represent a very sensitive diagnostic approach for clinical evaluation of disease progression

The expression of inhibitor of bruton's tyrosine kinase gene is progressively up regulated in the clinical course of chronic lymphocytic leukaemia conferring resistance to apoptosis.

Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy with a variable clinical outcome. Biomarkers of CLL progression are required for optimising prognosis and therapy. The Inhibitor of Bruton's tyrosine kinase-isoform α (IBTKα) gene encodes a substrate receptor of Cullin 3-dependent E3 ubiquitin ligase, and promotes cell survival in response to the reticulum stress. Searching for novel markers of CLL progression, we analysed the expression of IBTKα in the peripheral blood B-cells of CLL patients, before and after first line therapy causing remission. The expression of IBTKα was significantly increased in disease progression, and decreased in remission after chemotherapy. Consistently with a pro-survival action, RNA interference of IBTKα increased the spontaneous and Fludarabine-induced apoptosis of MEC-1 CLL cells, and impaired the cell cycle of DeFew B-lymphoma cells by promoting the arrest in G0/G1 phase and apoptosis. Consistently, RNA interference of IBTKα up regulated the expression of pro-apoptotic genes, including TNF, CRADD, CASP7, BNIP3 and BIRC3. Our results indicate that IBTKα is a novel marker of CLL progression promoting cell growth and resistance to apoptosis. In this view, IBTKα may represent an attractive cancer drug target for counteracting the therapy-resistance of tumour cells

Insights into Thymus Development and Viral Thymic Infections

T-cell development in the thymus is a complex and highly regulated process, involving a wide variety of cells and molecules which orchestrate thymocyte maturation into either CD4+ or CD8+ single-positive (SP) T cells. Here, we briefly review the process regulating T-cell differentiation, which includes the latest advances in this field. In particular, we highlight how, starting from a pool of hematopoietic stem cells in the bone marrow, the sequential action of transcriptional factors and cytokines dictates the proliferation, restriction of lineage potential, T-cell antigen receptors (TCR) gene rearrangements, and selection events on the T-cell progenitors, ultimately leading to the generation of mature T cells. Moreover, this review discusses paradigmatic examples of viral infections affecting the thymus that, by inducing functional changes within this lymphoid gland, consequently influence the behavior of peripheral mature T-lymphocytes