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Objectives: Most strategies for delirium prevention in older hospitalized patients are common good clinical geriatric care. We investigated whether acute geriatric ward (AGW) hospitalization, compared with acute general medical ward (AGMW) hospitalization,is associated with reduced incident delirium in older medical inpatients.Design: prospective observational study.Setting: a tertiary care, university hospital in Torino.Participants: consecutive medical patients 70 years or older admitted from the emergency department to an AGW and to an AGMW were included.Measurements: Baseline measures included demography, functional and psychocognitive status, comorbidity, physiological and clinical severity of acute illness. Incident delirium was evaluated by qualified psychiatrists according to the Confusion Assessment Method and the Delirium Rating Scale.Results: Delirium occurred in 8 of 121 patients admitted to AGW (6.6%) and in 20 of 131 patients admitted to AGMW (15.2%). After adjustment for significant differences in baseline covariates between groups, AGW hospitalization remained independently associated with less incident delirium (relative risk 0.90, 95% confidence interval: 0.024-0.331, p <0.001). In a multivariable logistic model with delirium incidence as independent variable, AGW hospitalization was independently associated with lower delirium incidence (relative risk 0.039, 95% confidence interval: 0.007-0.214, p <0.001), whereas greater cognitive impairment (p <0.001), higher Acute Physiology and Chronic Health Evaluation II score (p 0.001) and recent stressful events (p <0.001) were associated with increased delirium incidence.Conclusion: AGW hospitalization is associated with less incident delirium among older medical inpatients. Despite inherent limitations of observational studies, these hypothesis-generating findings add to previous evidence of potential benefit in delirium prevention from geriatric consultation in several hospital settings. [ABSTRACT FROM AUTHOR]

OBJECTIVES AND METHODS: We investigated the association of serum dehydroepiandrosterone sulfate (DHEA-S) levels with dementia of Alzheimer's type (DAT) and impairment in selected cognitive domains (memory, language, attention and working memory) in 158 patients (75.5 +/- 6.7 years, 46 men) with first-diagnosed probable DAT and in 158 age- and sex-matched controls. As secondary goal, we evaluated whether DHEA-S baseline levels were associated with cumulative 6-year mortality. RESULTS: A negative correlation between DHEA-S levels and age was observed (R = -0.25, p < 0.001). Age-stratified analysis did not show significant differences of DHEA-S levels between DAT patients and controls. No significant association was found between DHEA-S levels and impairment in selected cognitive domains. Cox regression analysis showed that baseline DHEA-S levels were not associated with cumulative 6-year mortality. CONCLUSIONS: In a sample of newly-diagnosed DAT patients, we did not find significant association between presence of DAT or impairment in cognitive domains and DHEA-S levels; baseline DHEA-S levels are not associated with cumulative mortality in patients and controls. Copyright (c) 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: The risk of cognitive decline in patients undergoing carotid endarterectomy (CE) for left internal carotid artery (ICA) (LICA) disease before or after the occurrence of ischemic symptoms has not been fully elucidated. We evaluated whether patients undergoing CE for symptomatic LICA stenosis have greater risk of cognitive decline than patients with asymptomatic LICA disease or right ICA disease. Methods: In a series of patients aged 65 years and older, consecutively undergoing CE and free from cognitive impairment, cognitive function was evaluated through the age- and education-adjusted Mini Mental State Examination and the Clock Drawing Task at baseline and at the end of the study period (average follow-up: 44.4 +/- 14.3 months). Results: The analysis included 103 patients (mean age 72.6 +/- 7.0 years; 73 men), of whom 50 had LICA disease (29 symptomatic). At the end of the study period, Mini Mental State Examination score was reduced in patients with symptomatic LICA disease (P < .001) but not in other patients, whereas the Clock Drawing Task score was reduced in both patients with LICA and right ICA. Patients with symptomatic LICA disease had greater risk of cognitive decline than other individuals, either measured by the Mini Mental State Examination score (F = 5.18, P = .002) or by the Clock Drawing Task score (F = 9.42, P = .001). Conclusions: Patients undergoing CE for symptomatic LICA disease appear to be at increased risk of cognitive decline than other individuals. Further studies are needed to confirm these findings and to evaluate whether LICA endarterectomy before occurrence of cerebrovascular ischemic symptoms may provide additive benefit in the prevention of cognitive decline. Copyright © 2005 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the in vitro immunomodulatory effects of zoledronic acid (Zol) on peripheral blood V?9/Vd2 (?d) T cells of normal donors and multiple myeloma (MM) patients.?dT cells were stimulated with Zol and low doses of interleukin-2 (IL-2), and then analyzed for proliferation, cytokine production, and generation of effector activity against myeloma cell lines and primary myeloma cells. Proliferation of?dT cells was observed in 100%of normal donors and 50%of MM patients.?dT cells produced IFN-?, surface mobilized the CD107a and CD107b antigens, and exerted direct cell-to-cell antimyeloma activity irrespective of the ability to proliferate to Zol and IL-2. The memory phenotype was predominant in the MM?dT cells that proliferated in response to Zol (responders), whereas effector cells were predominant in those that did not (nonresponders). Zol induced antimyeloma activity through the monocyte-dependent activation of?dT cells and by enhancing the immunosensitivity of myeloma cells to?dT cells. Mevastatin, a specific inhibitor of hydroxy-methylglutaryl-CoA reductase, completely abrogated this antimyeloma activity.Leukemia (2005) 19, 664-670. doi:10.1038/sj.leu.2403693 Published online 3 March 2005 [ABSTRACT FROM AUTHOR]

Several trials have shown the superior impact of high-dose melphalan (usually 200?mg/m2, MEL200) vs standard therapy in myeloma patients. Intermediate-dose melphalan (100?mg/m2, MEL100) is also superior to the standard dose, but has not been clinically compared with MEL200. A total of 90 patients at diagnosis were treated with two MEL100 courses. Their clinical outcome was compared with that of a control group of 90 pair mates matched for serum ß2-microglobulin levels and Durie and Salmon clinical stage. These patients were treated at diagnosis with two MEL200 courses. Patient characteristics were similar in both groups except that the median age of the MEL100 group was significantly higher (P<0.0001). Complete remission was 35% after MEL100 and 48% after MEL200 (P=0.08). Median event-free survival (EFS) was 32 months in the MEL100 group and 42 months in the MEL200 group (P<0.005), but overall survival (OS) was not different. Transplant-related mortality was not significantly different. Haematological and extra-haematological toxicity was significantly reduced after MEL100. Despite the significant age difference, tandem MEL100 was less toxic than tandem MEL200, and MEL100 was inferior to MEL200 in terms of EFS but not in terms of OS. The intensified nonmyeloablative MEL100 regimen is an effective first-line treatment.Leukemia (2004) 18, 133-138. doi:10.1038/sj.leu.2403196 Published online 30 October 2003 [ABSTRACT FROM AUTHOR]

Ecto-5'nucleotidase (5'NT), adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP) and deoxycytidine (CdR), deoxyguanosine (GdR), deoxyadenosine (AdR) and adenosine (AR) kinases have been measured in subpopulations of peripheral blood lymphocytes of eight healthy volunteers. The separation of B, T, T helper/inducer and T suppressor/cytotoxic cells was performed by means of density gradient centrifugation, E rosetting, passage through a nylon-wool column and antibody affinity chromatography utilising OKT8 and OKT4 monoclonal antibodies. ADA was significantly higher in T lymphocytes and 5'NT in B lymphocytes. Among T cell subpopulations, 5'NT activity was significantly higher (P < 0.01) in T suppressor/cytotoxic (OKT8+) cells (32.9 units/106 cells than in T helper/inducer (OKT4+) cells (9.7 units/106 cells). Indeed, the 5'NT activity in T suppressor cells was similar to that in B cells. T helper cells tended, however, to have higher PNP and ADA activities than T suppressor cells but the differences were not statistically significant. No major differences were noted in kinase activities between any of the lymphocyte subpopulations. [ABSTRACT FROM AUTHOR]

The recombinant interleukin-2 (rIL-2) generation of lymphokine-activated killer (LAK) cells was investigated in peripheral blood T lymphocytes (PBT) of 16 patients with monoclonal gammopathy of undetermined significance (MGUS) and 32 patients with multiple myeloma (MM). LAK activity was significantly decreased in MM, but not in MGUS patients. and was partially recovered in MM in the remission phase. This finding was unexpected, because CD8+ CD11b+ cells. which contain LAK precursors, are significantly increased in MM. LAK activity was investigated in purified CD8+ CD11 b+ lymphocytes to discriminate between an intrinsic defect or a defective regulation by other T cell subsets. These cells were intrinsically unable to generate LAK activity fully following rIL-2 stimulation. MM showed the more pronounced LAK deficiency, while MGUS patients showed intermediate values. Phenotyping revealed significantly increased proportions of Leu7+ and HLA-DR+ cells in MM patients. These data reveal another dysregulation of T cell effector functions in patients with monoclonal gammopathies and offer further evidence of the impairment of their cell-mediated immunity. [ABSTRACT FROM AUTHOR]

The generaton of cytotoxic T lymphocytes (CTL) towards allogeneic cells was investigated in 19 patients with monoclonal gammopathy of undetermined significance (MGUS) and 31 patients with multiple myeloma (MM). This function was significantly decreased in all patients. The cytotoxic deficiency was more pronounced in MM with poor prognosis than MM with good prognosis and MGUS patients. A phenotypic analysis of PBT lymphocytes showed that poor prognosis MM also had the highest proportions of activated cells (HLA-DR+) in CD8+ subpopulations. CTL were generated after depletion of CD11+ lymphocytes (including suppressor cells) or after inhibition of suppressor function with deoxyguanosine. No increase of cytotoxicity was detected under these conditions. Exogenous supplementation of recombinant interleukin 2 (rIL-2) was also ineffective. These data indicate that MG PBT lymphocytes are unable to fully differentiate into CTL following allogeneic stimulation. This deficiency is most evident in MM patients already showing the poorest prognosis and the most altered T cell phenotype. [ABSTRACT FROM AUTHOR]

In this study, 5'NT activity was investigated by radiochemical and cytochemical assays in T cell subpopulations of patients with multiple myeloma (MM). Cytotoxic/suppressor (CD8) and helper/inducer (CD4) lymphocytes were separated from peripheral blood by the panning technique, or sorted with a fluorescin activated cell sorter. 5'NT activity was significantly decreased in MM CD8 lymphocytes compared with the controls. By contrast, it was comparably low in CD4 subpopulations of normal controls and MM patients. The cytochemical assay indicated that a decreased number of 5'NT cells rather than a decreased activity per cell was responsible for 5'NT deficiency in MM CD8 lymphocytes. CD8 lymphocytes with the suppressor phenotype (OKM1+, granular cells) were significantly increased in MM. These data provide a phenotypic explanation for the enhanced suppressor activity displayed by T lymphocytes in MM. A significant correlation was found between the increase of suppressor cells and the decrease of 5'NT' cells. 5'NT deficiency of CD8 lymphocytes can be a biochemical marker for the expansion of suppressor T cells. [ABSTRACT FROM AUTHOR]

Four monoclonal IgGk gammopathies were studied with anti-idiotypic sera and the percentage of lymphocytes bearing such idiotypes was evaluated with a fluorescence activated cell sorter (FACS). A large percentage (10-15%) of peripheral lymphocytes bearing receptors with the same idiotypic specificities as the M component was observed in multiple myeloma (MM) und in monoclonal gammopalhy of undetermined significance (MGUS), suggesting a malignant origin for both these diseases, Capping-endocytosis and resynthesis experiments showed that these idiotypic receptors were not simply adsorbed on the cell membrane, but actually synthesized by the cells bearing them. Experiments performed after effective conventional chemotherapy showed a strong reduction of the idiotypic compartment in only one MM patient. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) derives from malignant transformation of plasma cells (PC), which accumulate in the bone marrow (BM), where microenvironment supports tumor growth and inhibits anti-tumor immune responses. Adenosine (ADO), an immunosuppressive molecule, is produced within MM patients' BM by adenosinergic ectoenzymes, starting from ATP (CD39/CD73) or NAD+ [CD38/CD203a(PC-1)/CD73]. These ectoenzymes form a discontinuous network expressed by different BM cells. We investigated the expression and function of ectoenzymes on microvesicles (MVs) isolated from BM plasma samples of patients with MM, using asymptomatic forms of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) as controls. The percentage of MVs expressing ectoenzymes at high levels was higher when derived from MM patients than controls. BM CD138+ PC from MM patients expressed high levels of all ectoenzymes. Paired MVs samples confirmed a higher percentage of MVs with high ectoenzymes expression in MM patients than controls. Pooled MVs from MM patients or controls were tested for ADO production. The catabolism of ATP, NAD+, ADPR and AMP to ADO was higher in MVs from MM patients than in those from controls. In conclusion, our results confirmed the hypothesis that MVs in MM niche are main contributor of ADO production. The ability of MVs to reach biological fluids strongly support the view that MVs may assume diagnostic and pathogenetic roles. [ABSTRACT FROM AUTHOR]

Background: In this trial of the treatment of newly diagnosed multiple myeloma, we compared a protocol that entailed a hematopoietic stem-cell autograft followed by an allograft from an HLA-identical sibling with a protocol of tandem autografts.Methods: We enrolled 162 consecutive patients with newly diagnosed myeloma who were 65 years of age or younger and who had at least one sibling. All patients were initially treated with vincristine, doxorubicin, and dexamethasone, followed by melphalan and autologous stem-cell rescue. Patients with an HLA-identical sibling then received nonmyeloablative total-body irradiation and stem cells from the sibling. Patients without an HLA-identical sibling received two consecutive myeloablative doses of melphalan, each of which was followed by autologous stem-cell rescue. The primary end points were overall survival and event-free survival.Results: After a median follow-up of 45 months (range, 21 to 90), the median overall survival and event-free survival were longer in the 80 patients with HLA-identical siblings than in the 82 patients without HLA-identical siblings (80 months vs. 54 months, P=0.01; and 35 months vs. 29 months, P=0.02, respectively). Among patients who completed their assigned treatment protocols, treatment-related mortality did not differ significantly between the double-autologous-transplant group (46 patients) and the autograft-allograft group (58 patients, P=0.09), but disease-related mortality was significantly higher in the double-autologous-transplant group (43% vs. 7%, P<0.001). The cumulative incidence rates of grades II, III, and IV graft-versus-host disease (GVHD) combined and of grade IV GVHD in the autograft-allograft group were 43% and 4%, respectively. Overall, 21 of 58 patients (36%) were in complete remission after a median follow-up of 38 months (range, 10 to 72) after allografting. Of the 46 patients who received two autografts, 25 (54%) died.Conclusions: Among patients with newly diagnosed myeloma, survival in recipients of a hematopoietic stem-cell autograft followed by a stem-cell allograft from an HLA-identical sibling is superior to that in recipients of tandem stem-cell autografts. (ClinicalTrials.gov number, NCT00415987 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a disease of plasma cells that has fatal consequences. New insights into the biology of MM have identified molecular mechanisms that hold promise as therapeutic targets. Laboratory and preclinical studies have shown that intracellular regulatory proteins and functional interactions between MM cells and the bone-marrow microenvironment have a pivotal role in the growth, survival, drug resistance, and malignant progression of MM cells. New agents associated with molecular targets have prompted clinical investigators to design new treatment strategies initially for advanced MM and later for newly diagnosed MM, with encouraging preliminary results. Here, we discuss the mechanisms of action of these new rational drugs and the preliminary clinical outcomes of a new treatment regimen for MM. [ABSTRACT FROM AUTHOR]

Several trials have shown the superior impact of high-dose melphalan (usually 200?mg/m2, MEL200) vs standard therapy in myeloma patients. Intermediate-dose melphalan (100?mg/m2, MEL100) is also superior to the standard dose, but has not been clinically compared with MEL200. A total of 90 patients at diagnosis were treated with two MEL100 courses. Their clinical outcome was compared with that of a control group of 90 pair mates matched for serum ß2-microglobulin levels and Durie and Salmon clinical stage. These patients were treated at diagnosis with two MEL200 courses. Patient characteristics were similar in both groups except that the median age of the MEL100 group was significantly higher (P<0.0001). Complete remission was 35% after MEL100 and 48% after MEL200 (P=0.08). Median event-free survival (EFS) was 32 months in the MEL100 group and 42 months in the MEL200 group (P<0.005), but overall survival (OS) was not different. Transplant-related mortality was not significantly different. Haematological and extra-haematological toxicity was significantly reduced after MEL100. Despite the significant age difference, tandem MEL100 was less toxic than tandem MEL200, and MEL100 was inferior to MEL200 in terms of EFS but not in terms of OS. The intensified nonmyeloablative MEL100 regimen is an effective first-line treatment.Leukemia (2004) 18, 133-138. doi:10.1038/sj.leu.2403196 Published online 30 October 2003 [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) derives from malignant transformation of plasma cells (PC), which accumulate in the bone marrow (BM), where microenvironment supports tumor growth and inhibits anti-tumor immune responses. Adenosine (ADO), an immunosuppressive molecule, is produced within MM patients' BM by adenosinergic ectoenzymes, starting from ATP (CD39/CD73) or NAD+ [CD38/CD203a(PC-1)/CD73]. These ectoenzymes form a discontinuous network expressed by different BM cells. We investigated the expression and function of ectoenzymes on microvesicles (MVs) isolated from BM plasma samples of patients with MM, using asymptomatic forms of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) as controls. The percentage of MVs expressing ectoenzymes at high levels was higher when derived from MM patients than controls. BM CD138+ PC from MM patients expressed high levels of all ectoenzymes. Paired MVs samples confirmed a higher percentage of MVs with high ectoenzymes expression in MM patients than controls. Pooled MVs from MM patients or controls were tested for ADO production. The catabolism of ATP, NAD+, ADPR and AMP to ADO was higher in MVs from MM patients than in those from controls. In conclusion, our results confirmed the hypothesis that MVs in MM niche are main contributor of ADO production. The ability of MVs to reach biological fluids strongly support the view that MVs may assume diagnostic and pathogenetic roles. [ABSTRACT FROM AUTHOR]