The fivefold root of an ethics of surgery

Surgical ethics have generally been framed as general medical ethics applied to surgical contexts. This model is helpful, but may miss some of the special features of the surgical process and relationship. It is suggested in this paper that there are five categories of experience and relationship which are especially important in surgery — rescue, proximity, ordeal, aftermath and presence . The sense of rescue, the feeling of relational proximity, the ordeal and the aftermath of surgery are things which the patient experiences. Understanding these experiences allow surgeons to understand what may be asked of them in an ethical sense. Recognition of the reality and validity of each category in the surgical process highlights the importance of presence , the acts by which the surgeon demonstrates that he is present to the patient throughout the surgical process and its aftermath. While the teaching of communication skills may never compensate for insensitivity, the ideal of presence as virtue and duty can be taught by precept and example.     

Naive T cells are maintained by thymic output in early ages but by proliferation without phenotypic change after age twenty

Analysing T-cell receptor excision circle numbers in healthy individuals we find a marked change in the source of naive T cells before and after 20 years of age. The bulk of the naive T cell pool is sustained primarily from thymic output for individuals younger than 20 years of age whereas proliferation within the naive phenotype is dominant for older individuals. Over 90% of phenotypically naive T cells in middle age are not of direct thymic origin. Moreover, this change in source of naive T cells is accompanied either by an increased death rate of T cells from the thymus or reduced thymic export. Modelling of these processes shows that new naive T cells of a thymic origin have a half-life of approximately 50 days before this change occurs, and that either the life-span of recent thymic emigrants (but not necessarily of all naive cells) decreases approximately threefold in middle age, or thymic production drops by this same amount. The decay rate of T-cell receptor excision circle levels for individuals over 20 years of age is consistent with the decay rate of the productive thymus. Our modelling suggests that at age 25, thymic export is responsible for 20% of naive T-cell production and that this percentage decreases with the 15.7 year half-life of the productive thymus so that by age 55 only 5% of naive production arises from thymic export.     

Pyropheophorbide 2-deoxyglucosamide: a new photosensitizer targeting glucose transporters

To prepare near-infrared fluorescence imaging and photodynamic therapy agents targeted at glucose transporters, pyropheophorbide 2-deoxyglucosamide (Pyro-2DG) was synthesized and evaluated in a 9L glioma rat model. Fluorescence imaging studies demonstrate that Pyro-2DG is selectively accumulated in the tumor. Upon its photoactivation, we demonstrate that this agent efficiently causes selective mitochondrial damage to the region of a tumor that was photoirradiated after administration of this agent, but does not affect tissues photoirradiated in the absence of the agent or tissues treated with the agent that are not photoirradiated. Preliminary confocal microscopy studies suggest that Pyro-2DG is delivered and trapped in tumor cells via the GLUT/hexokinase pathway and therefore is useful both as a tumor-targeted NIR fluorescence imaging probe and as a PDT agent for the destruction of cancer.     

A model of molecular interactions on short oligonucleotide microarrays

High-density short oligonucleotide microarrays have become a widely used tool for measuring gene expression on a large scale. However, details of the mechanism of binding on microarrays remain unclear. Short oligonucleotide probes currently synthesized on microarrays are often ineffective as a result of limited sequence specificity or low sensitivity. Here, we describe a model of binding interactions on microarrays that reveals how probe signals depend on probe sequences and why certain probes are ineffective. The model indicates that the amount of nonspecific binding can be estimated from a simple rule. Using this model, we have developed an improved measure of gene expression for use in data analysis.     

Survival and Nodulating Ability of Indigenous and Inoculated Rhizobium leguminosarum biovar trifolii in Sterilized and Unsterilized Soil Treated with Sewage Sludge

Rhizobium leguminosarum biovar trifolii was detected in soil from 41 of 47 plots, within nine sewage sludge-treated sites with different soil characteristics and heavy metal contents. However, although population size varied widely, there was no consistent correlation with soil heavy metal concentration. Indigenous populations in 20 plots within four selected sites retained their ability to induce effective nodule formation after incubation of soil in the dark for 165 days. In sterilized (γ-irradiated) soil, Rhizobium survival varied from 0.01% to 95% depending on the soil sample and strain used. Metal-resistant strains with non-mucoid colonies survived less well than mucoid metal-sensitive strains. Received: 26 June 2000/Accepted: 31 July 2000     

A new method for the study of chylomicron kinetics in vivo

Our understanding of the metabolism of chylomicrons, the lipoprotein that transports dietary fat from the intestine to peripheral tissues, is incomplete. The present studies were conducted to determine whether a labeled intravenous lipid emulsion could be used to estimate chylomicron triglyceride (TG) rate of appearance (R(a)) and thereby quantify the rate of intestinal fat absorption. After an overnight fast, healthy volunteers (n = 6) sipped a (3)H-labeled drink over 6.5 h at a rate of 175 mg fat. kg(-1). h(-1). Beginning at hour 5, an HPLC-purified, (14)C-labeled lipid emulsion was infused intravenously for 90 min. During the study, plasma total and chylomicron TG concentrations increased from 100 +/- 21 to 237 +/- 40 mg/dl and from undetectable to steady-state levels of 35 +/- 13 mg/dl, respectively. After a minor correction for VLDL contamination, tracer-determined chylomicron TG R(a) was 175 +/- 30 mg. kg(-1). h(-1), equal to the presumed ingestion rate. In summary, a radiolabeled intravenous lipid emulsion is able to accurately estimate chylomicron TG R(a) and therefore can be used to measure in vivo fat absorption rates.     

Testosterone, endurance, and Darwinian fitness: natural and sexual selection on the physiological bases of alternative male behaviors in side-blotched lizards

The mechanistic bases of natural and sexual selection on physiological and behavioral traits were examined in male morphs of three colors of the side-blotched lizard, Uta stansburiana. Orange-throated males are aggressive and defend large territories with many females. Blue-throated males defend smaller territories with fewer females; however, blue-throated males assiduously mate guard females on their territory. Yellow-throated males do not defend a territory, but patrol a large home range. They obtain secretive copulations from females on the territories of dominant males. Males with bright orange throats had higher levels of plasma testosterone (T), endurance, activity, and home range size and concomitantly gained greater control over female home ranges than blue- or yellow-throated males. Experimentally elevating plasma T in yellow- and blue-throated males increased their endurance, activity, home range size, and control over female territories to levels that were seen in unmanipulated orange-throated males that had naturally high plasma T. However, the enhanced performance of orange-throated males is not without costs. Orange-throated males had low survival compared to the other morphs. Finally, some yellow-throated males transformed to a partial blue morphology late in the season and the endurance of these transforming yellow-throated males increased from early to late in the season. In addition, yellow-throated males that transformed to blue also had significantly higher plasma T late in the season compared to the plasma T earlier in the season. T appears to play an important role in the physiological changes that all three color morphs undergo during the process of maturation. In some yellow males, T plays an additional role in plastic changes in behavior and physiology late in the reproductive season. We discuss natural and sexual selection on physiological and behavioral traits that leads to the evolution of steroid regulation in the context of alternative male strategies.     

Immucillin-H binding to purine nucleoside phosphorylase reduces dynamic solvent exchange

The rate and extent of hydrogen/deuterium (H/D) exchange into purine nucleoside phosphorylase (PNP) was monitored by electrospray ionization mass spectrometry (ESI-MS) to probe protein conformational and dynamic changes induced by a substrate analogue, products, and a transition state analogue. The genetic deficiency of PNP in humans is associated with severe T-cell immunodeficiency, while B-cell immunity remains functional. Inhibitors of PNP have been proposed for treatment of T-cell leukemia, to suppress the graft-vs.-host response, or to counter type IV autoimmune diseases without destroying humoral immunity. Calf spleen PNP is a homotrimer of polypeptide chains with 284 amino residues, molecular weight 31,541. Immucillin-H inhibits PNP with a Kd of 23 pM when only one of the three catalytic sites is occupied. Deuterium exchange occurs at 167 slow-exchange sites in 2 h when no catalytic site ligands are present. The substrate analogue and product prevented H/D exchange at 10 of the sites. Immucillin-H protected 32 protons from exchange at full saturation. When one of the three subunits of the homotrimer is filled with immucillin-H, and 27 protons are protected from exchange in all three subunits. Deuterium incorporation in peptides from residues 132-152 decreased in all complexes of PNP. The rate and/or extent of deuterium incorporation in peptides from residues 29-49, 50-70, 81-98, and 112-124 decreased only in the complex with the transition state analogue. The peptide-specific H/D exchange demonstrates that (1) the enzyme is most compact in the complex with immucillin-H, and (2) filling a single catalytic site of the trimer reduces H/D exchange in the same peptides in adjacent subunits. The peptides most highly influenced by the inhibitor surround the catalytic site, providing evidence for reduced protein dynamic motion caused by the transition state analogue.