Ciglitizone and 15d PGJ2 induce apoptosis in Jurkat and Raji cells

Several studies have shown that PPARgamma agonists play a role in the regulation of lymphocytes function and apoptosis. However, the molecular mechanism(s) underlying the immunomodulatory effects of PPARgamma agonists are not defined yet. In this study, the effects of PPARgamma (15d PGJ2 and ciglitizone) ligands on proliferation, cytokine production and apoptosis of Jurkat and Raji cells (human T and B lymphocytes, respectively) were examined. Ciglitizone and 15d PGJ2 presented antiproliferative and cytotoxic effects on Jurkat and Raji cells as shown by [14C]-thymidine incorporation and cell viability assay. In addition, 15d PGJ2 inhibited cytokine production (IL-2 in Jurkat cells and IL-10 in Raji cells). The mechanism whereby PPARgamma agonists induced cytotoxicity is via apoptosis as shown by DNA fragmentation, nuclear condensation and phosphatidylserine externalization. The induction of apoptosis by ciglitizone and 15d PGJ2 on Jurkat and Raji cells may explain the suppression of cytokine production and the decrease in proliferation observed in both cell types. The apoptotic process was associated with a decrease in mitochondrial membrane potential and a marked down-regulation of the c-myc expression. These findings might play a key role in the apoptosis of T and B lymphocytes induced by PPARgamma agonists.     

The relationship of patient age to the pathobiology of the clonal myeloid diseases

The incidence of the major clonal myeloid diseases, clonal cytopenias, acute, subacute (oligoblastic), and chronic myelogenous leukemia, polycythemia vera, thrombocythemia, and idiopathic myelofibrosis increases in a log-linear manner from young adulthood through advanced age. In older patients, diseases requiring cytotoxic treatment are more difficult and less successful to manage because comorbid conditions and poor performance status are more prevalent, decreasing the tolerance to therapy and increasing the frequency of side effects. This age effect is highlighted by the dramatically less favorable outcome in older than younger patients with acute myeloid leukemia with similar "favorable" cytogenetic changes. In addition, in acute and subacute myeloid leukemia in older patients, the disease is intrinsically more resistant to therapy. Overexpression of drug resistance genes and unfavorable genetic mutations are more prevalent in older patients and provide evidence that acute myeloid leukemia is often qualitatively different in these patients. The gradient of age effects is continuous; the frequency of poor outcome increasing by decade (or less). The decline in survival becomes especially steep as quinquagenarians (50-year-olds) age to nonagenarians (90-year-olds). Although improved drug schedules have led to significant improvements in event-free survival in younger patients, these improvements have been far less evident in older patients. New approaches, especially the development of drugs aimed at new targets, will be required to obtain a high frequency of long-term remissions in older patients. Agents that reverse inherent cellular drug resistance, farnesyltransferase inhibitors, BCL-2 inhibitors, and FLT3 inhibitors are early examples of such approaches.     

Modified VAD and PSC-833 in the treatment of resistant or relapsing chronic lymphocytic leukemia (E4996): a trial of the Eastern Cooperative Oncology Group

BACKGROUND & METHOD: The role of multidrug resistance (MDR) was investigated in patients with relapsed chronic lymphocytic leukemia (CLL). PSC-833 was added to modified VAD (a 4-day infusion of vincristine, doxorubicin, with oral dexamethasone, every 3 weeks), in an attempt to improve the response rate (21%) in a prior study. Laboratory tests to determine MDR and apoptosis proteins were correlated with response. RESULTS: Two of the seven MDR-positive cases and one of the four MDR-negative patients achieved a partial response (no significant difference). No significant correlation with response was found in any of the laboratory tests for apoptosis. CONCLUSION: VAD plus PSC-833 had the same (21%) partial response rate as a prior ECOG study without PSC-833. No correlation of response with MDR or apoptosis testing was found. Other drug resistance factors must play a significant role in determining the response of relapsed patients with CLL.     

Simultaneous presence of endogenous retrovirus and herpes virus antigens has profound effect on cell-mediated immune responses: implications for multiple sclerosis

Retroviruses have been suggested as possible pathogenic factors in multiple sclerosis (MS), supported by the observation that endogenous retroviruses are activated in MS patients. Different members of the herpes family of which several are neurotropic have also been suggested as factors in MS pathogenesis. Further, interactions between retroviruses and herpes viruses have been implied in the development of MS. The objective of the study was investigation of cell-mediated immune responses of MS patients to retrovirus and herpes virus antigens, particularly antigen combinations, with analyses of the influence of retrovirus antigens on cellular immunological reactivity toward other viral antigens. Cellular immunity as measured by blast transformation assays was analyzed using freshly isolated peripheral blood mononuclear cells from 47 MS patients and 36 healthy volunteers. Combinations of the endogenous retrovirus HERV-H and herpes virus antigens resulted in highly increased cellular immune responses among both the MS patients and healthy subjects. The increase was synergistic in character in most samples. Very pronounced effects were obtained using HHV-6A and HSV-1 antigens. Blast transformation assays combining antigens from two different herpes viruses or combinations of measles and herpes antigens showed no synergy. The obtained data indicate a pronounced synergistic effect on the cellular immune response when retrovirus and herpes antigens are present together. The cause of the synergy is unknown so far. The effect on the immune response may influence the disease progression.     

Progression of coronary artery disease in non-ischemic dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is traditionally divided into ischemic and non-ischemic etiologies. We review data from clinical trials that suggest some patients in the latter subgroup develop ischemic complications including fatal myocardial infarction. However, the reasons for and magnitude of the effect are not known. Prospective screening studies and improved endpoint adjudication in clinical trials may be required to better delineate the degree to which the phenomenon occurs. Risk factor modification strategies should be applied to the non-ischemic DCM cohort, especially with continued improvements in survival rates in patients with heart failure.     

Musical experience and dementia. Hypothesis

BACKGROUND AND AIMS: Cognitively stimulating activities appear to protect against the development of dementing illness--playing a musical instrument may be one of these activities. Consistent with this notion, the aim of this study was to explore the hypothesis that dementia might be less common among orchestral musicians. METHODS: A cross-sectional survey of 23 older orchestral musicians who were former members of a single orchestra was carried out. Prior musical background, family history, and health history were obtained. A cognitive screen was administered in person or by telephone. Musicians were also queried regarding their awareness of living former orchestral colleagues with dementia. RESULTS: The mean age of participants was 76.9 +/- 6.8 (SD). No participant was aware of a living former or current orchestral member with either reported or suspected dementia. CONCLUSIONS: The results are consistent with the hypothesis that dementing illness may be less among orchestral musicians--possibly from a lifetime engaged in a cognitively stimulating endeavor.     

Practical utility of clinical prediction rules for suspected acute pulmonary embolism in a large academic institution

INTRODUCTION: In an attempt to standardize clinicians' approach to the determination of pretest probability (PTP) in pulmonary embolism (PE), two simplified scoring models have recently been proposed. We sought to determine the utility of these algorithms in patients with suspected PE in a large, tertiary, academic medical center. METHODS: We performed a retrospective analysis of 295 inpatients and outpatients from our institution who were evaluated for suspected PE. Pretest probability (PTP) was calculated using two previously formulated scoring systems by Wells et al. (Canadian score) and Wicki et al. (Geneva score). Our primary endpoint was the prevalence of PE within each strata of PTP. RESULTS: The prevalence of pulmonary embolism in our cohort was 30%. The prevalence of PE in the low, intermediate and high PTP groups using the Canadian score was 15.3% (95% CI 9.5-23.7%), 34.8% (95% CI 27.9-42.4%), and 47.2% (95% CI 32.0-63.0), respectively. When compared with the low PTP group, the odds ratios of the likelihood of PE was 2.95 (95% CI 1.56-5.59) in the intermediate PTP group and 4.95 (95% CI 2.11-11.64) in the high PTP. The Wicki analysis was divided into "Geneva pure" and "Geneva presumed", where the fractional inspired oxygen concentration was known and presumed to have been sampled on room air, respectively. Neither of the Geneva scores showed statistical significance in the prevalence of PE among the PTP groups. CONCLUSIONS: The Wells' clinical prediction score is easily applied and meaningfully risk stratifies patients with suspected PE. In our population, the Geneva score was less useful.     

Antibody-mediated interference with annexins in the antiphospholipid syndrome

Targeting of the annexin A5 anticoagulant shield may be a significant mechanism for thrombosis and pregnancy losses in APS. This may occur via high affinity antibodies that recognize phospholipid-binding proteins that are capable of interfering with the assembly of the annexin A5 shield on phospholipid surfaces or via direct recognition of annexin A5 by autoantibodies. In addition, antibodies against other members of the annexin family of proteins may also have pathogenic roles in APS. It is anticipated that further research will elucidate the biologic functions of these proteins and their roles in the aPL disease processes.