Linkage of circulating eosinophils to markers on chromosome 5q

Although peripheral blood eosinophilia is strongly associated with the risk of developing asthma, genetic determinants of eosinophilia have not been extensively studied. We used sib-pair analysis to assess linkage of circulating eosinophils (as a percent of total white blood cells [WBC]) to nine markers located in chromosome 5q31-33. The study was divided into two phases. Of 246 sib pairs available for the first phase, 35 were classified as low concordant (LC) (both sibs had <= 2% circulating eosinophils), 18 were defined as high concordant (HC) (both sibs had 5% or more circulating eosinophils), and 26 were defined as discordant (one sib had <= 2% and the other sib had 5% or more circulating eosinophils). Significant evidence for linkage among low concordant sib pairs was found for several markers in the region under study, with a peak for marker D5S500 (proportion of alleles shared identical by descent [ibd] = 0.68 +/- 0.05 [mean +/- SE], p = 0.0004). A cross-validating study was done in which an additional 19 sib pairs that were low concordant for circulating eosinophils were studied. Evidence for linkage was also observed in this subset. Results were independent of current wheezing, total serum IgE levels, and other potential confounders. A multipoint analysis done for all low-concordant sib pairs available showed that the maximal logarithm of the odds favoring genetic linkage (LOD) score (2.4, p = 0.0004) was observed in correspondence with marker D5S658. We conclude that a locus or loci may be present in chromosome 5q31-33 that controls for circulating eosinophils as a proportion of total WBC.     

Serum free and total insulin-like growth factor-I, insulin-like growth factor binding protein-1 and insulin-like growth factor binding protein-3 Levels in healthy elderly individuals. Relation to self-reported quality of health and disability

Numerous controlled trials have demonstrated the efficacy of specific immunotherapy, although its mechanism is not completely understood. Few studies have addressed the effects of immunotherapy on the release of mediators. We measured in vitro sulphidoleukotriene (sLT) and histamine release after specific stimulus (Dermatophagoides pteronyssinus or Lollium perenne) in a group of patients under immunotherapy (n = 35) and compared the results with those obtained in a group of allergic patients without immunotherapy (n = 57). SLT quantification was carried out by cellular stimulation allergen test (CAST)-ELISA and we measured the amount of histamine release using a fluorometric method. We found a significant (p < 0.05) reduction of allergen-specific mediator release on the group of patients under immunotherapy treatment. When we studied the group of patients sensitive to D. pteronyssinus we also observed a significant reduction in sLT release after the in vitro stimulus with anti-IgE. In vitro sLT production could be a good marker for follow-up immunotherapy. This study provides more evidence to support the immunological and cellular changes induced by immunotherapy.     

Glutamate-dependent astrocyte modulation of synaptic transmission between cultured hippocampal neurons

The idea that astrocytes merely provide structural and trophic support for neurons has been challenged by the demonstration that astrocytes can regulate neuronal calcium levels. However, the physiological consequences of astrocyte-neuron signalling are unknown. Using mixed cultures of rat hippocampal astrocytes and neurons we have determined functional consequences of elevating astrocyte calcium levels on co-cultured neurons. Electrical or mechanical stimulation of astrocytes to increase their calcium level caused a glutamate-dependent slow inward current (SIC) in associated neurons. Microinjection of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) into astrocytes to prevent the stimulus-dependent increase in astrocyte calcium level, blocks the appearance of the neuronal SIC. Pharmacological manipulations indicate that this astrocyte-dependent SIC is mediated by extracellular glutamate acting on N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors. Additionally, stimulation of astrocytes reduced the magnitude of action potential-evoked excitatory and inhibitory postsynaptic currents through the activation of metabotropic glutamate receptors. The demonstration that astrocytes modulate neuronal currents and synaptic transmission raises the possibility that astrocytes play a neuromodulatory role by controlling the extracellular level of glutamate.     

A vaccine and monoclonal antibodies that enhance mouse resistance to Candida albicans vaginal infection

We previously reported that a vaccine composed of liposome-mannan complexes of Candida albicans (L-mann) stimulates mice to produce protective antibodies against disseminated candidiasis. An immunoglobulin M (IgM) monoclonal antibody (MAb), B6.1, specific for a beta-1,2-mannotriose in the complexes protects against the disease, whereas MAb B6 does not. In the present study, the vaccine and MAbs B6.1 and B6 were tested for the ability to protect against Candida vaginal infection, established by intravaginal (i.vg.) inoculation of yeast cells in mice maintained in pseudoestrus. Fungal CFU in each vagina was determined to assess the severity of infection. Mice vaccinated before infection developed about 62% fewer vaginal CFU than nonimmunized controls. Naive mice that received polyclonal antiserum (from vaccinated mice) i.vg. before infection had 60% fewer CFU than controls. The serum protective factor was stable at 56 degreesC, but C. albicans cells absorbed this factor. Mice given MAb B6.1 i.vg. after infection was established had fewer Candida CFU in vaginal tissue than control mice given buffer instead of antibody. MAbs B6.1 and B6 given intraperitoneally before infection protected mice, but MAbs preabsorbed with yeast cells did not. MAb B6.1 also protected against C. tropicalis vaginal infection, but MAb B6 did not. The protective activities of MAbs B6.1 and B6 appeared to be specific because an irrelevant IgM carbohydrate-specific MAb and an irrelevant IgG protein-specific MAb were not protective; also, MAb B6.1 did not affect development of vaginal chlamydial infection. These studies show that an appropriate antibody response, or administration of protective antibodies, can help the host to resist Candida vaginal infection.     

Lysis of HIV-1-infected cells and inhibition of viral replication by universal receptor T cells

Increasing evidence suggests that HIV-1-specific cytotoxic T lymphocytes (CTLs) are a key host immune response to HIV-1 infection. Generation of CTL responses for prevention or therapy of HIV-1 infection has several intrinsic technical barriers such as antigen expression and presentation, the varying HLA restrictions between different individuals, and the potential for viral escape by sequence variation or surface molecule alteration on infected cells. A strategy to circumvent these limitations is the construction of a chimeric T cell receptor containing human CD4 or HIV-1-specific Ig sequences linked to the signaling domain of the T cell receptor zeta chain (universal T cell receptor). CD8+ CTLs transduced with this universal receptor can then bind and lyse infected cells that express surface HIV-1 gp120. We evaluated the ability of universal-receptor-bearing CD8+ cells from a seronegative donor to lyse acutely infected cells and inhibit HIV-1 replication in vitro. The kinetics of lysis and efficiency of inhibition were comparable to that of naturally occurring HIV-1-specific CTL clones isolated from infected individuals. Further study will be required to determine the utility of these cells as a therapeutic strategy in vivo.     

Socioeconomic factors, health behaviors, and mortality: results from a nationally representative prospective study of US adults

CONTEXT: A prominent hypothesis regarding social inequalities in mortality is that the elevated risk among the socioeconomically disadvantaged is largely due to the higher prevalence of health risk behaviors among those with lower levels of education and income. OBJECTIVE: To investigate the degree to which 4 behavioral risk factors (cigarette smoking, alcohol drinking, sedentary lifestyle, and relative body weight) explain the observed association between socioeconomic characteristics and all-cause mortality. DESIGN: Longitudinal survey study investigating the impact of education, income, and health behaviors on the risk of dying within the next 7.5 years. PARTICIPANTS: A nationally representative sample of 3617 adult women and men participating in the Americans' Changing Lives survey. MAIN OUTCOME MEASURE: All-cause mortality verified through the National Death Index and death certificate reviews. RESULTS: Educational differences in mortality were explained in full by the strong association between education and income. Controlling for age, sex, race, urbanicity, and education, the hazard rate ratio of mortality was 3.22 (95% confidence interval [CI], 2.01-5.16) for those in the lowest-income group and 2.34 (95% CI, 1.49-3.67) for those in the middle-income group. When health risk behaviors were considered, the risk of dying was still significantly elevated for the lowest-income group (hazard rate ratio, 2.77; 95% CI, 1.74-4.42) and the middle-income group (hazard rate ratio, 2.14; 95% CI, 1.38-3.25). CONCLUSION: Although reducing the prevalence of health risk behaviors in low-income populations is an important public health goal, socioeconomic differences in mortality are due to a wider array of factors and, therefore, would persist even with improved health behaviors among the disadvantaged.     

Cellular and molecular determinants of cisplatin resistance

Cisplatin and carboplatin are among the most active and widely used cytotoxic anticancer drugs. However, the acquisition or presence of resistance significantly undermines the curative potential of these drugs against many malignancies. Multiple potential mechanisms of resistance have been identified at the cellular and molecular levels. Alterations in cellular pharmacology, including decreased drug accumulation, increased cellular thiol levels and increased repair of platinum-DNA damage, have been observed in numerous model systems. More recently, it has become apparent that an enhanced capacity to tolerate cisplatin-induced damage may also contribute to resistance. Alterations in proteins that recognise cisplatin-DNA damage (mismatch repair and high-mobility group (HMG) family proteins) and in pathways that determine sensitivity to apoptosis may contribute to damage tolerance. It remains to be determined whether any of these mechanisms contribute significantly to resistance in the clinical setting. Ongoing biochemical modulation and translational correlative trials should clarify which specific mechanisms are most relevant to clinical cisplatin resistance. Such investigations have the potential to improve the ability to predict likelihood of response and should identify potential targets for pharmacological or molecular intervention.