Comparison of antibody repertoires against Staphylococcus aureus in healthy individuals and in acutely infected patients

The management of staphylococcal diseases is increasingly difficult with present medical approaches. Preventive and therapeutic vaccination is considered to be a promising alternative; however, little is known about immune correlates of protection and disease susceptibility. To better understand the immune recognition of Staphylococcus aureus by the human host, we studied the antistaphylococcal humoral responses in healthy people in comparison to those of patients with invasive diseases. In a series of enzyme-linked immunosorbent assay analyses performed using 19 recombinant staphylococcal cell surface and secreted proteins, we measured a wide range of antibody levels, finding a pronounced heterogeneity among individuals in both donor groups. The analysis revealed marked differences in the antibody repertoires of healthy individuals with or without S. aureus carriage, as well as in those of patients in the acute phase of infection. Most importantly, we identified antigenic proteins for which specific antibodies were missing or underrepresented in infected patients. In contrast to the well-described transient nature of disease-induced antistaphylococcal immune response, it was demonstrated that high-titer antistaphylococcal antibodies are stable for years in healthy individuals. In addition, we provide evidence obtained on the basis of opsonophagocytic and neutralizing activity in vitro assays that circulating antistaphylococcal serum antibodies in healthy donors are functional. In light of these data we suggest that proper serological analysis comparing the preexisting antibody repertoires of hospitalized patients with different outcomes for nosocomial staphylococcal infections could be extremely useful for the evaluation of candidate vaccine antigens in addition to protection data generated with animal models.     

Investigation of the role of the serotonergic activity of certain subtype-selective alpha1A antagonists in the relaxant effect on the pregnant rat uterus in vitro

Results from recent studies have shown that alpha(1A)-adrenergic receptor (alpha(1A)-AR) antagonists could offer a new alternative in the treatment of preterm delivery. However, members of this group [2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride (WB4101), 5-methylurapidil (5-MU)] are known to influence serotonin (5-hydroxy-tryptamine) (5-HT(1A)) receptors, too. Our objective was to clarify the role of their 5-HT(1A) activities in the uterus relaxant effect. RT-PCR was used to determine mRNA expression of the receptor subtypes in 22 day pregnant rat uteri. Isolated uteri were stimulated by 5-HT or electrical field to investigate the contraction-inhibiting effect and the 5-HT(1A) activity of the alpha(1A) antagonists. Both receptor subtypes are present in rat myometrium. 5-HT induced contractions were inhibited by the alpha(1A) antagonists. Besides shifting the dose-response curve of 5-HT to the right, 5-MU decreased its maximal effect. The alpha(1A) antagonists inhibited electrical field stimulation-induced contractions. 5-HT(1A) blockade increased the maximal effect of 5-MU but did not change that of WB4101. These results suggest that the contraction increase caused by 5-HT is mediated by alpha(1A) receptors. Serotonergic activity of alpha(1) antagonists and especially alpha(1A) antagonists should be investigated as it may alter their efficacy and could interfere with their side-effects. It is proposed that novel alpha(1A) antagonists should be designed with no 5-HT(1A) activity to achieve maximal relaxant effect.     

Genetic and cytological characterization of the RecA-homologous proteins Rad51 and Dmc1 of Schizosaccharomyces pombe

The Schizosaccharomyces pombe rad51⁺ and dmc1⁺ genes code for homologues of the Escherichia coli recombination protein RecA. Deletion of rad51⁺ causes slow growth, retardation of cell division and a decrease in viability. rad51 cells have a defect in mating-type switching. The DNA modification at the mating-type locus required for mating-type switching contributes to slow growth in the rad51 mutant. Cell mating is reduced in crosses homozygous for rad51. Ectopic expression of the dmc1⁺ gene allowed us to demonstrate that the reduction in meiotic recombination in dmc1 mutants is not caused by a disturbance of rad24 expression from the dmc1-rad24 bicistronic RNA. We describe the functional defects of terminally epitope-tagged Dmc1 and Rad51 and discuss it in terms of protein interaction. Presumptive Rad51 and Dmc1 foci were detected on spreads of meiotic chromatin.     

Interaction of plasma fibronectin (pFN) with membranous constituents of peritoneal exudate cells and pulmonary macrophages

The prominent role of plasma fibronectin (pFN) in the host defense system as an opsonin for gelatin (collagen)-coated colloids has been established. In the present study we investigated the interaction of pFN and membrane isolates from cells devoid of collagen, as well as several tissues. In a liver slice assay system it was shown that subcellular membrane fractions from lung macrophages, peritoneal exudate cells, spleen, tests, and liver were able to competitively inhibit the pFN-mediated uptake of 125I-gelatin coated latex beads (gLtx) at low concentrations. Endocytosis of 125I-labeled membrane isolates by macrophage monolayers was also promoted by addition of pFN. In an attempt to characterize the membrane component(s) interacting with pFN, it was found that mild extraction procedure with 1 M KBr could release a significant amount of this inhibitory activity. Further studies demonstrated that the agent(s) responsible for inhibition of gLtx uptake was heat sensitive, not altered by trypsin treatment, and did not contain actin, a protein known to interact with pFN. This work indicates that pFN interacts specifically with an as yet unknown membrane component(s) and that such interaction will promote clearance of cellular debris by macrophages. This suggests that pFN may be an important opsonin for the reticuloendothelial system in clearance of collagenous and noncollagenous cellular debris once they are exposed to interact with it.     

Immunocytotherapy. A new trend in fetal tissue transplantation

The clinical applications of theoretical immunology are not numerous. The authors demonstrate present-day immunocytotherapeutic approaches to fetal tissue transplantation widely used in medicine. Results of therapy by injections of lymphokine-activated killer cells in combination with interleukin-2, T-cell vaccines, and genetically transformed T cells are presented. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 117, N ^o 4, pp. 412–415, April, 1994     

The epithelial-mesenchymal transition induces aggressivity of mucinous cystic neoplasm of the pancreas with neuroendocrine component: An immunohistochemistry study

Background

Pancreatic mucinous cystic neoplasms (MCN) are rare tumors that are usually diagnosed in females.

The role of the thalamic reticular neurons in alpha- and gamma-oscillations in neocortex: a mechanism for selective perception and stimulus binding

The long-term objective is to understand how large masses of neurons in the brain process information during various learning and memory paradigms. Both time- and space-dependent processes have been identified in animals through computer-based analytic quantifications of event-related extracellular potentials. New nonlinear analyses have been introduced that presume that the fine-grain variation in the signal is determined and patterned in phase-space. Some neurons in the primary visual cortex manifest gamma-band oscillations. These cells show both a nonspecific phase-alignment (response synchrony) and a specific tuning (orientation tuning) when stimuli are presented to their receptive fields. This dual regulation of the sensory cells is proposed to underlie stimulus binding, a theoretical mechanism for "object" perception. Nonlinear analytic results from gamma-activities in a simple model neuropil (olfactory bulb) suggest that neuroplasticity may arise through self-organization, a process in which a nonlinear change in the dynamics of the oscillatory field potentials is the hallmark. This self-organization may follow simple dynamical laws in which global cooperativity among the neurons is transiently brought about that, over trials, results in enduring changes in the nonlinear dynamics of some neurons. In conclusion, the sculpturing of the synaptic throughput in the sensory cortex (stimulus binding) may be associated with the irregular phases of the gamma-activities and may result from both specific and nonspecific systems operating together in a nonlinear self-organizing manner.     

Activation of metabotropic glutamate receptors does not alter the phosphorylation state of GluR1 AMPA receptor subunit at serine 845 in perirhinal cortical neurons

Activation of group I and group II metabotropic glutamate receptors (mGluRs) is thought to be required for long-term depression (LTD) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor-mediated synaptic transmission in the perirhinal cortex. However, little is known about how activation of mGluRs leads to this form of synaptic plasticity. AMPA receptor phosphorylation has been implicated in several forms of modulation of synaptic transmission. In the CA1 area of the hippocampus, N-methyl-d-aspartate (NMDA) receptor-dependent LTD is associated with the reduced phosphorylation of the GluR1 AMPA receptor subunit at serine 845 (GluR1-S845). Immunoblot analysis of perirhinal cortical neurons using GluR1 and GluR1-S845 phosphorylation state specific antibodies showed that stimulation of adenylyl cyclase (AC) with forskolin (FSK) dramatically increased PKA-mediated phosphorylation of GluR1-S845. However, selective or simultaneous application of mGluR5 agonist (S)-3,5-dihydroxyphenylglycine (CHPG) and mGluR2/3 agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG IV) did not produce detectable changes in GluR1-S845 phosphorylation. These results indicate that in the perirhinal cortex mGluR activation does not alter the phosphorylation state of GluR1-S845. Therefore, it is likely that the process involved in the modification of AMPA receptors in mGluR activation dependent LTD in the perirhinal cortex is mechanistically distinct from NMDA receptor-mediated LTD described in hippocampal neurons.     

Kidney recipients with allograft failure,transition of kidney care (KRAFT): A survey of contemporary practices of transplant providers

Kidney allograft failure and return to dialysis carry a high risk of morbidity. A practice survey was developed by the AST Kidney Pancreas Community of Practice workgroup and distributed electronically to the AST members. There were 104 respondents who represented 92 kidney transplant centers. Most survey respondents were transplant nephrologists at academic centers. The most common approach to immunosuppression management was to withdraw the antimetabolite first (73%), while only 12% responded they would withdraw calcineurin inhibitor (CNI) first. More than 60% reported that the availability of a living donor is the most important factor in their decision to taper immunosuppression, followed by risk of infection, risk of sensitization, frailty, and side effects of medications. More than half of respondents reported that embolization was either not available or offered to less than 10% as an option for surgical intervention. Majority reported that ≤50% of failed allograft patients were re-listed before dialysis, and less than a quarter of transplant nephrologists performed frequent visits with their patients with failed kidney allograft after they return to dialysis. This survey demonstrates heterogeneity in the care of patients with a failing allograft and the need for more evidence to guide improvements in clinical practice related to transition of care.     

Prevention and management of infection in trauma

Examination of the causes of late mortality in multiple trauma patients reveals that as much as 78% of all deaths may be attributed to septic complications, suggesting the value of understanding the prevention and treatment of traumatic sepsis. In penetrating trauma, the protective features of the skin are eliminated, and systemic mechanisms of host defense are compromised. These changes in the host defense mechanism and the risk of infection influence the choice and technical features of wound closure and the use of antibiotics. Early diagnosis is imperative, but difficult.