Aseptic meningitis due to varicella-zoster virus: serum antibody levels and local synthesis of specific IgG, IgM, and IgA

We used an indirect enzyme immunoassay to describe the evolution of serum levels and the intrathecal production of IgG, IgA, and IgM antibodies to varicella-zoster virus (VZV) in eight patients with a syndrome of acute aseptic meningitis (AAM) and evidence of intrathecal production of VZV-specific IgG antibodies. Four of the eight patients showed no cutaneous zoster while hospitalized. Our results suggested an etiologic relation between VZV and AAM in all cases. Furthermore, we observed some differences in the pattern of evolution of antibodies in serum and cerebrospinal fluid in relation to the presence or absence of cutaneous lesions in our patients. These differences could reflect different pathogenic mechanisms in the spread of VZV to the central nervous system and in the production of the AAM syndrome.     

Risk factors for hepatocellular carcinoma in Catalonia, Spain

The influence of hepatitis B virus infection, alcohol consumption, tobacco smoking and use of oral contraceptives on the risk of hepatocellular carcinoma (HCC) was evaluated in a hospital-based case-control study in Catalonia, in the Mediterranean coastal area of north-eastern Spain. A total of 96 HCC cases (86.5% of them with associated liver cirrhosis) and 190 age- and sex-matched controls were studied. The odds ratio of HCC and 95% confidence interval among hepatitis B surface antigen (HBsAg) carriers was 4.9 (1.3-21.9). The OR was not significantly elevated in smokers, and a marginally significant increased risk was found among users of oral contraceptives based on 6 female cases. There was a significant dose-response relationship between alcohol consumption and risk of HCC (chi 2 for trend: 24.3, p less than 0.001). Although hepatitis B infection was strongly associated with HCC, alcohol abuse leading to cirrhosis appears to be one of the main causes of HCC in this region.     

Inhibition of T-tropic HIV Strains by Selective Antagonization of the Chemokine Receptor CXCR4

Bicyclams are a novel class of antiviral compounds that are highly potent and selective inhibitors of the replication of HIV-1 and HIV-2. Surprisingly, however, when the prototype compound AMD3100 was tested against M-tropic virus strains such as BaL, ADA, JR-CSF, and SF-162 in human peripheral blood mononuclear cells, the compound was completely inactive. Because of the specific and potent inhibitory effect of AMD3100 on T-tropic viruses, but not M-tropic viruses, it was verified that AMD3100 interacts with the CXC-chemokine receptor CXCR4, the main coreceptor used by T-tropic viruses. AMD3100 dose dependently inhibited the binding of a specific CXCR4 monoclonal antibody to SUP-T1 cells as measured by flow cytometry. It did not inhibit the binding of the biotinylated CC-chemokine macrophage inflammatory protein (MIP) 1α or MIP-1β, ligands for the chemokine receptor CCR5 (the main coreceptor for M-tropic viruses). In addition, AMD3100 completely blocked (a) the Ca²⁺ flux at 100 ng/ml in lymphocytic SUP-T1 and monocytic THP-1 cells, and (b) the chemotactic responses of THP-1 cells induced by stromal cell–derived factor 1α, the natural ligand for CXCR4. Finally, AMD3100 had no effect on the Ca²⁺ flux induced by the CC-chemokines MIP-1α, regulated on activation normal T cell expressed and secreted (RANTES; also a ligand for CCR5), or monocyte chemoattractant protein 3 (a ligand for CCR1 and CCR2b), nor was it able to induce Ca²⁺ fluxes by itself. The bicyclams are, to our knowledge, the first low molecular weight anti-HIV agents shown to act as potent and selective CXCR4 antagonists.The bicyclam derivatives were described several years ago as potent and selective inhibitors of HIV type 1 and type 2 replication (1, 2). AMD3100, previously called JM3100 (2) or SID791 (3), exhibits anti-HIV potency at concentrations of 1–10 ng/ml, with a selectivity index ⩾100,000 (2). Based on time-of-addition experiments, the compound has been assumed to interact with the HIV fusion-uncoating process, but does not inhibit virus binding to the CD4 receptor (1, 2). AMD3100 blocks syncytium formation at a concentration that is 10–100-fold higher than the concentration required to inhibit virus infection (1). The env glycoprotein (gp)120 has been considered the major target molecule for this class of compounds because, for viruses that were made resistant to the bicyclams, a number of mutations accumulated in the gp120, especially in the V3-V4 region (3, 4).Numerous publications over the last year have demonstrated the importance of chemokine receptors for HIV entry. Chemokines are chemotactic cytokines, which are classified as CC or CXC, depending on the positioning of conserved cysteine residues. Fusin/LESTR, now designated CXC-chemokine receptor 4 (CXCR4), mediates entry of T-tropic viruses (5, 6) which can be inhibited by its natural ligand, the CXC-chemokine stromal cell–derived factor 1α (SDF-1α) (7, 8). The CC-chemokine receptor, CCR5, mediates entry of M-tropic viruses (9–13) and the CC-chemokines regulated on activation normal T cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP) 1α and MIP-1β have been shown to inhibit the replication of M-tropic viruses (14). Moreover, M-tropic env proteins can interact directly with CCR5 (15, 16).In previous studies AMD3100 was shown to inhibit the replication of T-tropic HIV strains or clinical isolates in T cell lines (such as MT-4, MOLT-4, or CEM cells; references 1–4). While verifying whether AMD3100 was active against M-tropic viruses in PBMCs, we found that AMD3100 does not inhibit M-tropic viruses such as BaL, ADA, JR-CSF, and SF-162. Here we show that AMD3100 selectively inhibits the binding of a CXCR4-specific mAb, but not the binding of biotinylated human MIP-1α or MIP-1β. The bicyclam was also found to inhibit the Ca²⁺ flux and the chemotactic response induced by SDF-1α but not such effects induced by RANTES, MIP-1α, or monocyte chemoattractant protein 3 (MCP-3).     

Does a better grade of tumour occurring in women under hormone replacement therapy compensate for their lower probability of detection by screening mammography

OBJECTIVE: To compare the prognostic factor of breast cancer survival between breast cancer diagnosed in subjects receiving hormone replacement therapy (HRT) before diagnosis to those without such a therapy. Subjects and methods: All breast cancers diagnosed between 1993 and 2000 within the breast cancer screening programme in Bouches du Rh?ne (France) were analysed for size, node status, and grade according to use, or not, of HRT. Univariate and multivariate analyses were carried out taking into account age, density of the breast, and mode of detection. RESULTS: The breast tumours diagnosed among HRT users had a lower grade whatever the mode of detection. The proportion of node positive tumours was identical in the two groups after adjustment for age. The smaller size of the tumours among HRT users is partly explained by the lower grade of these tumours Conclusion: Although tumours occurring in HRT users have a lower chance of being detected by screening, their prognostic factors, especially the grade of the tumour, are better than in non-users. More work is needed to find which part of this advantage is attributable to better surveillance of women treated with HRT     

Analysis of malaria associated genetic traits in Cabo Verde,a melting pot of European and sub Saharan settlers

Malaria has occurred in the Cabo Verde archipelago with epidemic characteristics since its colonization. Nowadays, it occurs in Santiago Island alone and though prophylaxis is not recommended by the World Health Organization, studies have highlight the prospect of malaria becoming a serious public health problem as a result of the presence of antimalarial drug resistance associated with mutations in the parasite populations and underscore the need for tighter surveillance.Despite the presumptive weak immune status of the population, severe symptoms of malaria are not observed and many people present a subclinical course of the disease. No data on the prevalence of sickle-cell trait and red cell glucose-6-phosphate dehydrogenase deficiency (two classical genetic factors associated with resistance to severe malaria) were available for the Cabo Verde archipelago and, therefore, we studied the low morbidity from malaria in relation to the particular genetic characteristics of the human host population. We also included the analysis of the pyruvate kinase deficiency associated gene, reported as putatively associated with resistance to the disease.Allelic frequencies of the polymorphisms examined are closer to European than to African populations and no malaria selection signatures were found. No association was found between the analyzed human factors and infection but one result is of high interest: a linkage disequilibrium test revealed an association of distant loci in the PKLR gene and adjacent regions, only in non-infected individuals. This could mean a more conserved gene region selected in association to protection against the infection and/or the disease.