A transient granulocyte killing defect secondary to a varicella infection

A varicella infection in a previously healthy young girl was complicated by bacterial sepsis, arthritis, and osteomyelitis in multiple locations. This secondary complication caused by Staphylococcus aureus was associated with a transient defect in granulocyte function and an alteration in the representation of CD4 and CD8 positive lymphocyte subpopulation. The mechanism responsible for secondary bacterial infections following varicella may be due to transient defects in granulocyte function.     

Industry-funded dermatologic research within academia in the United States: fiscal and ethical considerations.

Private-sector funding of biomedical research within academia may come from industry, foundations, the dermatologists themselves, and the public at large. Industry-funding is of benefit to both academia and industry. Industry may fund clinical and basic research and product testing. Industry is more willing to fund product testing and clinical research than basic research. Funds for dermatologic research may be obtained from manufacturers of drugs, medical devices, cosmetics, soaps, and detergents. Questions of academic freedom arise when research is funded by industry. The results of academic research are in the public domain; the results of intramural industry research are often proprietary, i.e., "trade secrets." When there is industry funding within academia, any restraints on publication should be held to a minimum and be temporary. Publication should occur in a timely fashion, although recognizing the need for delayed publication if the results concern patentable material. When there is a consultantship, pre-arranged terms of agreement may restrict communication. Patents usually are held by the investigator's institution. The funding company may be granted world-wide, royalty-bearing licenses. Conflicts of interest may arise during any research endeavor; this warrants close attention when the research is industry funded. Stock ownership, speaker fees, blind contracts, etc., should be avoided. In any communication, funding agreements should be stated. Indirect costs are a "necessary evil." There are non-research expenditures associated with all research projects for which the institution is justified in requesting compensation. Indirect costs must have definite connections to a project. As industrial funding of research within academia increases, various facets of the academia-industry relationship are receiving increasing attention. Several aspects of conflicts of interest and indirect costs must yet be resolved. When faced openly and directly, all of these issues are manageable and need not reduce the benefits to both industry and academia that are inherent in this relationship. Federal funding of academic research uses tax dollars; industry funding comes from private capital. Academia will benefit from the funding of academic biomedical research by industry. The ultimate beneficiary of the funding of academic research by industry, however, will be society at large as the medical advances derived from sound biomedical research and carefully controlled clinical trials aid patients. A solidly established academia-industry relationship is essential to the effective funding by industry of biomedical research within academia.     

Social psychology, contexts of aging, and a contextual world view

Two world views-mechanism and organicism-have dominated the youthful history of social psychological study of adult development and aging. Despite differences, both assume a stable, universal, transhistorical structure underlying social psychology; the goal of research is to discover and delineate such universals. A third world view, contextualism, begins with an assumption that action and thought are developed within relationships, which form the contexts for particular actions. It stresses the negotiated, constructed nature of "reality,"the historical embeddedness and unique quality of action as it unfolds, and the importance of negotiation making use of multiple perspectives. The approach and contextualist goals are significantly different from more typical approaches. Three areas of research in social gerontology and social psychology-environmental relations, attribution, and social relations in a social reconstruction/social breakdown model-illustrate a contextualist approach. Control and a "voice" in a negotiation of relationships and the characteristics of one's contexts are central to a contextual approach to all three.     

Aquaporin-1 and HCO3−-Cl− transporter-mediated transport of CO2 across the human erythrocyte membrane

Recent studies have suggested that aquaporin-1 (AQP1) as well as the HCO₃⁻-Cl⁻ transporter may be involved in CO₂ transport across biological membranes, but the physiological importance of this route of gas transport remained unknown. We studied CO₂ transport in human red blood cell ghosts at physiological temperatures (37 °C). Replacement of inert with CO₂-containing gas above a stirred cell suspension caused an outside-to-inside directed CO₂ gradient and generated a rapid biphasic intracellular acidification. The gradient of the acidifying gas was kept small to favour high affinity entry of CO₂ passing the membrane. All rates of acidification except that of the approach to physicochemical equilibrium of the uncatalysed reaction were restricted to the intracellular environment. Inhibition of carbonic anhydrase (CA) demonstrated that CO₂-induced acidification required the catalytic activity of CA. Blockade of the function of either AQP1 (by HgCl₂ at 65 μM) or the HCO₃⁻-Cl⁻ transporter (by DIDS at 15 μM) completely prevented fast acidification. These data indicate that, at low chemical gradients for CO₂, nearly the entire CO₂ transport across the red cell membrane is mediated by AQP1 and the HCO₃⁻-Cl⁻ transporter. Therefore, these proteins may function as high affinity sites for CO₂ transport across the erythrocyte membrane.     

Analysis of tetanus toxin peptide/DR recognition by human T cell receptors reconstituted into a murine T cell hybridoma

We have previously reported that human T cell receptors (TcR) selected in the class II-restricted (HLA-DRB1*1302) response to a tetanus toxin peptide (tt830-843) frequently used the Vβ2 germ-line segment which paired with several Vα segments and that the putative CDR3 of both α and β chains showed remarkable heterogeneity. To analyze the structural basis for recognition of the tt830-843/DR complex, five of these TcR were reconstituted into a murine T cell hybridoma, 58 α^?β^?, by expressing the human α and β variable regions joined to the mouse α and β constant regions, respectively. The chimeric TcR, expressing the same Vβ germ-line segment (Vβ2), two expressing Vα21.1, twoVα17.1 and one Vα8.1 were shown to have the expected antigen specificity and DR restriction. Two lines of evidence suggested that the putative CDR3, although not conserved in these TcR, played a key role in recognition. First, two TcR with identical V germ-line segments but distinct CDR3 showed large differences in their capacity to react with the ligand. Second, interchanging the α and β chains from tt830-843/DR1302-specific TcR which differed in their CDR3 sequences invariably led to loss of recognition. We also asked whether germ-line Vα17.1 could functionally replace Vα21.1, as they appear to be related in their primary sequence. However, as in the case of CDR3 exchanges, Vα replacement abrogated TcR reactivity. Taken together, these data underline the fine interdependence of the structural components of the TcR binding site in defining a given specificity. Four of the TcR studied displaying promiscuous recognition were also tested against different DR alleles and site-directed mutants. The results of these experiments suggested that, in spite of their structural heterogeneity, anti-tt830-843 TcR may have a similar orientation with respect to the peptide/DR complex. The reconstitution system described herein should represent a valuable tool for detailed studies of human TcR specificity.     

Solid-phase radioimmunoassay for detection of plague antigen in animal tissue.

A rapid and sensitive radioimmunoassay for the detection of soluble Yersinia pestis fraction I antigen using antibody-coated beads and radiolabeled immunoglobulin was applied to spleen-liver extracts, rendered noninfectious by either treatment or filtration, from rodents dead of plague. The procedure was capable of detecting nanogram amounts of soluble plague antigen.     

Metabolic functions of duplicate genes in Saccharomyces cerevisiae

The roles of duplicate genes and their contribution to the phenomenon of enzyme dispensability are a central issue in molecular and genome evolution. A comprehensive classification of the mechanisms that may have led to their preservation, however, is currently lacking. In a systems biology approach, we classify here back-up, regulatory, and gene dosage functions for the 105 duplicate gene families of Saccharomyces cerevisiae metabolism. The key tool was the reconciled genome-scale metabolic model iLL672, which was based on the older iFF708. Computational predictions of all metabolic gene knockouts were validated with the experimentally determined phenotypes of the entire singleton yeast library of 4658 mutants under five environmental conditions. iLL672 correctly identified 96%-98% and 73%-80% of the viable and lethal singleton phenotypes, respectively. Functional roles for each duplicate family were identified by integrating the iLL672-predicted in silico duplicate knockout phenotypes, genome-scale carbon-flux distributions, singleton mutant phenotypes, and network topology analysis. The results provide no evidence for a particular dominant function that maintains duplicate genes in the genome. In particular, the back-up function is not favored by evolutionary selection because duplicates do not occur more frequently in essential reactions than singleton genes. Instead of a prevailing role, multigene-encoded enzymes cover different functions. Thus, at least for metabolism, persistence of the paralog fraction in the genome can be better explained with an array of different, often overlapping functional roles.     

Human serum IgE-mediated mast cell degranulation shows poor correlation to allergen-specific IgE content

BACKGROUND: Although allergen-specific IgE content in serum can be determined immunochemically, little is known about the relationship between this parameter and the strength of the degranulation response upon allergen triggering. OBJECTIVES: Analyse the degranulation capacity of immunochemically defined purified and serum IgE after challenge with anti-IgE or allergen using a rat mast cell line (RBL) transfected with the alpha-chain of the human high-affinity IgE receptor (FcepsilonRI). METHODS: Purified IgE specific for 4-hydroxy-3nitrophenylacetyl, purified IgE of unknown specificity, and sera from allergic patients sensitive to Dermatophagoides pteronyssinus and Dactylis glomerata were assessed. Degranulation was measured by a beta-hexosaminidase release assay after anti-IgE or allergen-specific challenge. RESULTS: For purified monoclonal IgE a significant correlation (r = 0.97) was found between the proportion of bound allergen-specific IgE and the strength of the degranulation response. In contrast, no correlation (r = 0.27) was detected after sensitization with serum IgE. CONCLUSION: Our studies demonstrate that mast cell activation mediated through IgE from allergic patients is a result of complex relationships that are not only dependent on allergen-specific IgE content but also relate to the capacity to efficiently sensitize and trigger the signalling responses that lead to degranulation.