NK cell activity controls human herpesvirus 8 latent infection and is restored upon highly active antiretroviral therapy in AIDS patients with regressing Kaposi's sarcoma

Kaposi's sarcoma (KS) develops upon reactivation of human herpesvirus 8 (HHV8) infection and virus dissemination to blood and tissue cells, including endothelial and KS spindle cells where the virus is mostly present in a latent form. However, this may likely require the presence of compromised host immune responses and/or the evasion of infected cells from the host immune response.In this regard, mechanisms of evasion of productively infected cells from both CTL and NK cell responses, and resistance of latently infected cells from specific CTL, have already been shown. Here we show that cells which are latently infected by HHV8 are indeed efficiently lysed by NK cells from individuals with a normal immune response. Notably, NK cell-mediated immunity was found to be significantly reduced in AIDS patients with progressing KS as compared to both HIV-negative patients with indolent classic KS or normal blood donors. However, it was restored after treatment with the highly active antiretroviral therapy (HAART) in AIDS-KS patients, that showed regression and clearance of HHV8 from PBMC. By contrast, AIDS-KS patients with a more aggressive disease and no clinical response had persistent HHV8 viremia associated with reduced NK cell cytotoxicity. These results suggest a key role for NK cells in the control of HHV8 latent infection, KS development, and in disease remission upon HAART.     

Decreased T cell apoptosis and T cell recovery during highly active antiretroviral therapy (HAART)

T cell apoptosis represents a common mechanism of T cell depletion in HIV-1-infected individuals reflecting maturational and functional T cell abnormalities either directly or indirectly induced by the virus. In the present study, the effects of highly active antiretroviral therapy (HAART) on the spontaneous apoptosis of distinct T cell subsets were investigated during a 6-month follow-up in a cohort of HIV-1-infected individuals with CD4(+) cell counts between 100 and 500 cells/microliter and plasma HIV-1 RNA levels >/=10, 000 copies/ml. We determined that the rapid and sustained increase of both naive (CD45RA(+)CD62L(+)) and memory (CD45R0(+) and CD45RA(+)/CD62L(-)) CD4(+) and, to as lesser extent, CD8(+) T cells in peripheral blood was associated with a significant decrease of apoptotic CD4(+) and CD8(+) as well as CD3(+)CD4(-)CD8(-) T cells. Among CD4(+) lymphocytes, at enrollment, the highest frequency of apoptotic cells was observed within the memory compartment, as defined by CD45R0 expression. During HAART, however, the frequency of CD4(+)CD45R0(+) apoptotic T cells progressively decreased in association with a significant downregulation of surface activation markers that indicated decreased levels of systemic immune stimulation. These results indicate that effective viral suppression can contribute to progressive normalization of maturational and functional T cell abnormalities responsible for the high levels of T cell apoptosis in HIV-1-infected individuals. This, in turn, may contribute to a reduced rate of T cell loss and immune reconstitution during HAART.     

Occupational injuries in Italy

Data collected by the Italian Funds for Occupational Injuries and Diseases (INAIL) on incidence and mortality for occupational injuries in Italy during 1951-2001 are described with respect to the two main occupational sectors, Industry and Services, and Agriculture. Comparisons with other EU countries are included to place the current severe phenomenon in context. An ad hoc analysis aimed at verifying the completeness of the data on occupational fatal accidents collected by INAIL in Tuscany is reported: a linkage between the INAIL data and those registered by the Tuscan Regional Mortality Registry highlights that a number of working areas are not covered by INAIL, a problem whose solution would be useful for primary prevention.     

Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells

Gemcitabine and pemetrexed are effective agents in the treatment of non-small-cell lung cancer (NSCLC), and the present study investigates cellular and genetic aspects of their interaction against A549, Calu-1, and Calu-6 cells. Cells were treated with pemetrexed and gemcitabine, and their interaction was assessed using the combination index. The role of drug metabolism in gemcitabine cytotoxicity was examined with inhibitors of deoxycytidine kinase (dCK), 5'-nucleotidase, and cytidine deaminase, whereas the role of pemetrexed targets, thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT) in drug chemosensitivity was analyzed in cytotoxicity rescue studies. The effect of gemcitabine and pemetrexed on Akt phosphorylation was investigated with enzyme-linked immunosorbent assay, whereas quantitative polymerase chain reaction (PCR) was used to study target gene-expression profiles and its modulation by each drug. Synergistic cytotoxicity was demonstrated, and pemetrexed significantly decreased the amount of phosphorylated Akt, enhanced apoptosis, and increased the expression of dCK in A549 and Calu-6 cells, as well as the expression of the human nucleoside equilibrative transporter 1 (hENT1) in all cell lines. PCR demonstrated a correlation between dCK expression and gemcitabine sensitivity, whereas expression of TS, DHFR, and GARFT was predictive of pemetrexed chemosensitivity. These data demonstrated that 1) gemcitabine and pemetrexed synergistically interact against NSCLC cells through the suppression of Akt phosphorylation and induction of apoptosis; 2) the gene expression profile of critical genes may predict for drug chemosensitivity; and 3) pemetrexed enhances dCK and hENT1 expression, thus suggesting the role of gene-expression modulation for rational development of chemotherapy combinations.     

From Binswanger's disease to leuokoaraiosis: what we have learned about subcortical vascular dementia

The literature regarding subcortical vascular dementia associated with periventricular and deep white matter alterations is reviewed. Information pertaining to neuropathological, neuropsychological, and neuroradiological studies is emphasized. Based on this review and prior neuropsychological studies associating subcortical vascular pathology with greater deficits on tests of executive dysfunction and with relatively better performance on tests of delayed recognition memory, we conclude that vascular dementia associated with periventricular and deep white matter alterations can and should be regarded as a subcortical dementing illness. Also, we support schemes suggested by Erkinjuntti et al. (2000) and Cosentino et al. (this issue) that attempt to integrate neuropsychological and neuroradiological data into a diagnostic paradigm that describes, as well as diagnoses, dementing disorders. We discuss questions and issues about vascular dementia that deserve further consideration and study.     

Combined therapy for selected chronic uremic patients: infrequent hemodialysis and nutritional management

The results are described of a combined nutritional (supplemented diet) and dialytic (once a week hemodialysis) therapy, employed in 17 selected chronic uremics for a mean period of 18.2 months/patient. The clinical findings, blood chemical abnormalities and changes of renal function were examined and compared with those of patients on the standard thrice-a-week dialysis schedule and free diet. The clinical findings were not significantly different in the two groups. The residual renal function of patients on combined therapy declined faster than in patients on conservative treatment, but at a slower rate than in those on thrice-a-week dialysis. The time averages of serum urea, methylguanidine and phosphate concentrations and their postdialytic rebounds were lower in the patients on combined therapy than in those on thrice-a-week dialysis, whereas the time averages of the serum creatinine concentration were higher, and those of serum bicarbonate and serum oxalate were not significantly different in the two groups. It is concluded that this combined therapy is a valid alternative to the conventional thrice-a-week hemodialysis and free diet for selected patients and for periods of time whose duration is conditioned by the rate of decline of the residual renal function.