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Objective: Although bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) is well recognized, little is known about it in terms of pathophysiology, epidemiology or management. We analyzed all suspected BRONJ reports sent to the Italian Pharmacovigilance Adverse Event Spontaneous Reporting System (Rete Nazionale Farmacovigilanza [RNF]) to determine their pattern and add new information about this relevant issue., Research Design and Methods: All suspected BRONJ sent to the RNF between 2003 and 2011 were retrieved. After a case-by-case assessment procedure, we analyzed BP type, BP exposure time and time since last use., Results: Between 2003 and 2011, 555 reports of osteonecrosis of the jaw (ONJ) after BP administration were recorded in the RNF. These events occurred mostly in patients affected by cancer (77.84%) in which zoledronate was the most frequently suspected BP. Most patients experienced ONJ after long-term use of the drug (median time of BP exposure being between 1.3 and 8.8 years). Interestingly, 139 (25.05%) cases of ONJ occurred between 2 and 121 months after BP withdrawal., Conclusion: This study shows that BRONJ can occur much earlier than hitherto reported, adds new data on BRONJ onset following ibandronate treatment and reveals that patients who cease BP-based therapy develop ONJ, raising the question of post-treatment monitoring strategies.

Purpose: To evaluate the effect of a broad range of covariates on the survival of a real-life long-term follow-up cohort of community-dwelling patients with behavioural and psychological symptoms of dementia who were new users of atypical antipsychotic medications (APMs)., Methods: This was a prospective cohort study of 1,618 subjects aged ≥65 years with dementia and BPSD ("behavioural and psychological symptoms of dementia") who were new users of atypical APMs and registered in a Dementia Evaluation Unit of Campania Region (Italy) from September 2006 to March 2010. The potential of baseline features to predict mortality was assessed with the Cox proportional hazards model., Results: The average follow-up was 309 days. Of the 1,618 new users of atypical antipsychotics, 9.3 % experienced at least one adverse event, including death (5.1 %), drug therapeutic failure (3.0 %), extrapyramidal symptoms (0.5 %) and stroke (0.2 %). The crude all-cause mortality rate was 6.0 per 100 person-years [95 % confidence interval (CI) 4.8-7.4]; the rate was higher in patients aged >85 years (9.0 per 100 person-years, 95 % CI 6.4-12.7) and among male patients (7.5 per 100 person-years, 95% CI 5.3-10.6). In the multivariate analysis, only age was associated to all-cause mortality [hazard ratio (HR) 1.1; 95 % CI 1.0-1.1 and HR 1.4; 95 % CI: 0.9-2.2, respectively). In contrast, hallucination (HR 0.4; 95 % CI 0.2-0.6) and dosage change (HR 0.4; 95 % CI 0.2-0.78) were significantly associated with a lower risk of all-cause mortality., Conclusions: Among our patient cohort, the mortality rate of patients with BPSD receiving long-term treatment with atypical APMs was lower than that reported in other studies, and only age was found to be significant predictor factor of mortality.

According to European recommendations, the Italian Medicines Agency (AIFA) required close monitoring of the safety of the MF59-adjuvanted H1N1v vaccine, which was the only vaccine available in Italy for prophylaxis of the A/H1N1 (2009) pandemic influenza. From October 2009 to June 2010, the Italian Pharmacovigilance Adverse Event (AE) Spontaneous Reporting System [Rete Nazionale Farmacovigilanza] (RNF) received 1330 reports of AEs temporally related with the pandemic influenza vaccination out of a total of 924,057 doses administered. Among these, 1,162 (87.37%) AE reports were classified 'non serious', 91 (6.84%) 'serious', 3 (0.23%) had a fatal outcome and 74 (5.56%) did not include the degree of seriousness. Among the serious AE reports, some unexpected AEs emerged. Even though some typical vaccine safety issues which emerged should be further explored, such as vaccination in pregnancy, the analysis of all AE reports sent to RNF shows that the vaccine has a well-tolerated safety profile which resembles that of the already available seasonal influenza vaccines. This contrasts with the widespread public concern about its safety, which has been one of the major causes of the low vaccination rate observed in Italy, as well as in other countries., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

To study naive and memory CD8 T cell turnover, we performed BrdU incorporation experiments in adult thymectomized C57BL/6 mice and analyzed data in a mathematical framework. The following aspects were novel: 1) we examined the bone marrow, in addition to spleen and lymph nodes, and took into account the sum of cells contained in the three organs; 2) to describe both BrdU-labeling and -delabeling phase, we designed a general mathematical model, in which cell populations were distinguished based on the number of divisions; 3) to find parameters, we used the experimentally determined numbers of total and BrdU(+) cells and the BrdU-labeling coefficient. We treated mice with BrdU continuously via drinking water for up to 42 days, measured by flow cytometry BrdU incorporation at different times, and calculated the numbers of BrdU(+) naive (CD44(int/low)) and memory (CD44(high)) CD8 T cells. By fitting the model to data, we determined proliferation and death rates of both subsets. Rates were confirmed using independent sets of data, including the numbers of BrdU(+) cells at different times after BrdU withdrawal. We found that both doubling time and half-life of the memory population were approximately 9 wk, whereas for the naive subset the doubling time was almost 1 year and the half-life was roughly 7 wk. Our findings suggest that the higher turnover of memory CD8 T cells as compared with naive CD8 T cells is mostly attributable to a higher proliferation rate. Our results have implications for interpreting physiological and abnormal T cell kinetics in humans.

By comparing mature CD8-cell turnover in different organs, we previously demonstrated that CD8 cells proliferate predominantly in the bone marrow (BM). To investigate the mechanisms underlying such increased turnover, we compared BM, lymph nodes, and spleen CD8 cells from untreated C57BL/6 mice regarding in vivo proliferation within the organ; in vitro response to interleukin-7 (IL-7), IL-15, IL-21; ex vivo expression of membrane CD127 (IL-7Ralpha), intracellular Bcl-2, phospho-STAT-5 (signal transducer and activator of transcription 5), phospho-p38 mitogen activated protein kinase (MAPK); and in vivo proliferation on adoptive transfer. In the BM, the proliferation rate was increased for either total CD8 cells or individual CD44 and CD122 subsets. In contrast, purified CD8(+) cells from the BM did not show an enhanced in vitro proliferative response to IL-7, IL-15, and IL-21 compared with corresponding spleen cells. After transfer and polyinosinic-polycytidylic acid (polyI:C) treatment, both spleen-derived and BM-derived CD8 cells from congenic donors proliferated approximately twice more in the recipient BM than in spleen and lymph nodes. Our results suggest that BM CD8 cells are not committed to self-renewal, but rather are stimulated in the organ. Molecular events constantly induced in the CD8 cells within the BM of untreated mice include increase of both phosphorylated STAT-5 and phosphorylated p38 intracellular levels, and the reduction of CD127 membrane expression.

Long-term persistence of Ag-experienced CD8 cells, a class of T lymphocytes with cytotoxic function, contributes to immunological memory against intracellular pathogens. After Ag clearance, memory CD8 cells are maintained over time by a slow proliferation, primarily cytokine driven. In this article, we show that the bone marrow (BM) is the crucial organ where such basal division of memory CD8 cells occurs. BM memory CD8 cells contain a higher percentage of proliferating cells than their corresponding cells in either spleen or lymph nodes from C57BL/6 mice. This occurs both in the case of memory-phenotype CD44(high) CD8 cells and in the case of Ag-specific memory CD8 cells. Importantly, the absolute number of Ag-specific memory CD8 cells dividing in the BM largely exceeds that in spleen, lymph nodes, liver, and lung taken together. In the BM, Ag-specific memory CD8 cells express lower levels of CD127, i.e., the alpha-chain of IL-7R, than in either spleen or lymph nodes. We interpret these results as indirect evidence that Ag-specific memory CD8 cells receive proliferative signals by IL-7 and/or IL-15 in the BM and propose that the BM acts as a saturable "niche" for the Ag-independent proliferation of memory CD8 cells. Taken together, our novel findings indicate that the BM plays a relevant role in the maintenance of cytotoxic T cell memory, in addition to its previously described involvement in long-term Ab responses.