Meningococcal disease in Italy in 1989

Meningococcal disease in Italy decreased by 13.4% from 1988 to 1989. The incidence rate was 0.5/100,000 in the general population and 1.3/100,000 in army recruits. The highest proportion of cases (27%) was seen in subjects 5-14 years old. The sex ratio was 1.3. Forty-four percent of the isolates belonged to serogroup B; 37% belonged to group C. Forty-six percent of the strains were resistant to sulphonamides and 10% were resistant to minocycline; only 4% were resistant to rifampicin. None of the four military cases observed could be attributed to vaccine failure. One secondary case and no coprimary cases were observed among civilians. The shift in prevalence from serogroup C to serogroup B isolates is the most important finding of this study.     

Relative increase of T cells expressing the gamma/delta rather than the alpha/beta receptor in ataxia-telangiectasia

In ataxia-telangiectasia, B-cell and T-cell deficiencies are thought to be due to a defect of rearrangements of immunoglobulin and T-cell receptor genes. T cells recognize antigens through two types of CD3-associated receptors: alpha/beta chains on mature cells and gamma/delta chains mostly on immature cells. We studied 10 patients with ataxia-telangiectasia and found that most had a relative increase of circulating T cells bearing gamma/delta receptors rather than alpha/beta receptors, as compared with normal subjects (P less than 0.001). Patients with other immune deficits, including eight with common variable immunodeficiency, one with Wiskott-Aldrich syndrome, two with hyperimmunoglobulinemia E syndrome, and one with severe combined immunodeficiency, had normal ratios of gamma/delta-bearing to alpha/beta-bearing cells. A marked predominance of gamma/delta-bearing T cells was found in a patient with a primary T-cell defect. The relative increase in gamma/delta-bearing T cells in the patients with ataxia-telangiectasia was largely accounted for by cells that reacted with the monoclonal antibody BB3, an apparently distinct subset of T cells that selectively express the C gamma 1 gene product of the T-cell receptor. Although they had normal ratios of gamma/delta-bearing to alpha/beta-bearing T cells, the patients with common variable immunodeficiency had a significant increase (P = 0.01) in the number of T cells expressing C gamma 2 that reacted with the monoclonal antibody delta-TCS-1. We conclude that the increased ratio of gamma/delta-bearing to alpha/beta-bearing T cells in ataxia-telangiectasia may reflect both a recombinational defect that interferes with T-cell and B-cell gene rearrangements and an inability to repair damage to the DNA.     

Hypogammaglobulinemia with hyper-IgM, severe T-cell defect, and abnormal recirculation of OKT4 lymphocytes in a girl with chronic lymphadenopathy

We describe here one 8-year-old girl with an unusual form of immunodeficiency, characterized by hypogammaglobulinemia with hyper-IgM, severe T-cell defect, and chronic lymphadenopathy. Patient's B cells failed to produce IgG or IgA in vitro following stimulation with either pokeweed mitogen or Epstein-Barr virus, suggesting an intrinsic B-cell defect. Abnormal T-cell function was demonstrated by impaired in vivo delayed type hypersensitivity, reduction of mitogen-induced proliferation and interleukin 2 production, reduction of interferon-gamma production, and marked decrease of circulating OKT4+ cells. The latter cells were found in normal proportion in the patient's lymph node tissue. This finding suggests that the decrease of OKT4+ cells in peripheral blood was due to the abnormal recirculation of these cells. The identity of this syndrome with the infantile form of the acquired immunodeficiency syndrome was apparently ruled out by the failure to demonstrate HTLV-III-related sequences in patient's lymphocytes or virus-specific serum antibodies.     

IgM and IgG antibodies to human T cell lymphotropic retrovirus (HTLV-III) in lymphadenopathy syndrome and subjects at risk for AIDS in Italy

A study was performed to assess the prevalence of specific antibodies to human T cell lymphotropic retrovirus (HTLV-III) in patients with lymphadenopathy syndrome, patients with the acquired immune deficiency syndrome (AIDS), and those at risk of AIDS. Serum samples were obtained from these groups and from healthy controls in selected cities in Italy, and antibodies to HTLV-III were measured by immunofluorescence assay and, in a few patients, by Western blotting. In addition, IgM antibody values were measured in 82 of those positive for HTLV-III. Altogether, 235 out of 320 patients with lymphadenopathy syndrome had antibodies to HTLV-III, the proportions being highest in haemophiliacs, homosexuals, and drug addicts from Rome; 11 out of 12 patients with AIDS had antibodies; 78 out of 439 subjects at risk for AIDS had antibodies; and six out of 30 patients with lymphadenopathy syndrome and positive for HTLV-III antibodies and nine of 52 patients at risk of AIDS had a detectable titre of IgM. HTLV-III is widespread in groups at risk of AIDS in Italy, and antibodies to HTLV-III are highly prevalent in patients with lymphadenopathy syndrome. A higher proportion of drug abusers were positive for antibodies than in previous studies. HTLV-III "infection" would appear to be spread mainly in compromised hosts, as none of the controls were positive for antibodies.     

The ventromedial hypothalamus mediates predator fear memory

The amygdala has been shown to be essential for the processing of acute and learned fear across animal species. However, the downstream neural circuits that mediate these fear responses differ according to the nature of the threat, with separate pathways having been identified for predator, conspecific and physically harmful threats. In particular, the dorsomedial part of the ventromedial hypothalamus (VHMdm) is critical for the expression of defensive responses to predators. Here, we tested the hypothesis that this circuit also participates in predator fear memory by transient pharmacogenetic inhibition of the VMHdm and its downstream effector, the dorsal periaqueductal grey, during predator fear learning in the mouse. Our data demonstrate that neural activity in the VMHdm is required for both the acquisition and recall of predator fear memory, whereas that of its downstream effector, the dorsal periaqueductal grey, is required only for the acute expression of fear. These findings are consistent with a role for the medial hypothalamus in encoding an internal emotional state of fear.     

In vitro effect of aspartame in angiogenesis induction

Aspartame (APM) is the most widely used artificial sweetener and is added to a wide variety of foods, beverages, drugs, and hygiene products. In vitro and in vivo tests have reported contradictory data about APM genotoxicity. We evaluated the angiogenic effect of APM in an in vitro model using blood vessel development assay (Angio-Kit), cultured endothelial cells and fibroblasts. The release of IL-6, VEGF-A, and their soluble receptors sIL-R6 and sVEGFR-2 were determined over time in the conditioned medium of the Angio-Kit system, endothelial cells and cell lines with fibroblast properties after APM treatment. Reactive oxygen species (ROS) formation, cell viability, and stimulation of the extracellular signal-regulated kinases (erk1/2) and protein p38 were also evaluated. Exposure to APM induced blood vessel formation. ROS production was observed in endothelial cells after APM treatment, which was associated with a slight cell cytotoxicity. Neither intracellular ROS formation nor cell death was observed in fibroblasts. APM increases the levels of inflammatory mediator IL-6, VEGF and their soluble receptors released from endothelial cells into the medium. APM treatment induces VEGF-pathway activation by erk1/2 and p38 phosphorylation. APM at low doses is an angiogenic agent that induces regenerative cytokine production leading to the activation of MAPKs and resulting in the formation of new blood vessels.     

Activation of alpha-diacylglycerol kinase is critical for the mitogenic properties of anaplastic lymphoma kinase

Oncogenic rearrangements of the tyrosine kinase receptor anaplastic lymphoma kinase (ALK), most commonly represented by the nucleophosmin/ALK fusion protein (NPM/ALK), are involved in the pathogenesis of anaplastic large-cell lymphomas (ALCLs). In an effort to identify new intracellular transducers operative in ALK-positive malignancies, we have investigated the potential involvement of diacylglycerol kinase (DGK). Here we show that alphaDGK is constitutively activated in the NPM/ALK-positive ALCL-derived cell line Karpas 299 and in NPM/ALK-infected 32D hematopoietic cells. These results were further validated in fibroblastic NIH-3T3 cells expressing a previously described chimeric epidermal growth factor receptor (EGFR)/ALK molecule that allows dissection of ALK enzymatic function under conditions of controlled ligand-induced activation. In this cell system, we also show that ALK-mediated alphaDGK activation is dependent on p60src tyrosine kinase, with which alphaDGK forms a complex. The specific inhibition of alphaDGK, obtained by cell treatment with R59949, significantly reduced cellular growth in all cell lines. This result was further confirmed in Karpas 299 cells following specific down-regulation of alphaDGK by RNA interference. Overall, our data indicate that alphaDGK activation is involved in the control of ALK-mediated mitogenic properties.