Effects of surgery on the pharmacokinetic parameters of drugs

As with other forms of stress, surgery is a time of fluctuating haemodynamics, physiological shifts, intense metabolic changes, and protein catabolism and anabolism. At times, these changes can occur within hours. There is a reasonable body of literature concerning the adverse effects of surgery on gastric emptying, but not on the effects of surgery on the distribution, metabolism and excretion of drugs. Gastric emptying is diminished or absent following major procedures, which prevent the delivery of orally administered drugs to their major site of absorption, the small bowel. Changes in the paracellular absorption of drugs may occur postoperatively, although transcellular absorption appears to be unimpaired. Distribution is affected by changes in blood volume, alterations in circulation, increases in the extracellular fluid and changes in the circulating plasma protein levels, such as albumin and alpha 1-acid glycoprotein. Little is known about alterations in drug metabolism following surgery. However, it has been shown that systemic hypoxia alters the function of some of the cytochrome P450 (CYP) system and increased levels of cytokines have an effect on the metabolism of at least 1 drug. In addition, the renal elimination of drugs is affected in patients postoperatively, although the effects of biliary clearance in this period are difficult to determine. Despite the lack of research into pharmacokinetics during the postoperative period, and given the immense and often sudden changes observed in patients post-surgery, it is reasonable to recommend vigilance with respect to drug therapy during this period.     

Anesthesia and analgesia for minor injuries to children

Today's children are rambunctious, playful, and aggressive and are provided through the miracles of modern technology with ample opportunities to injure themselves. As such, they are a source of both joy and terror to their parents. It is a "given" that many of them will injure themselves in the course of growing up. When they come to us in the ED waiting room, they are typically very frightened and usually in pain. We are fortunate that we have techniques and drugs to alleviate this pain and to attenuate their fear. It is our responsibility as anesthesiologists to ensure that these drugs and techniques are used appropriately and cause no further harm. We hope the information contained in this chapter may be of benefit in achieving this goal.     

Functional knockout of the transient outward current, long-QT syndrome, and cardiac remodeling in mice expressing a dominant-negative Kv4 alpha subunit

Amino acid changes S180A (S-->A at site 180), H197Y, Y277F, T285A, and A308S are known to shift the maximum wavelength of absorption (lambda max) of red and green visual pigments toward blue, essentially in an additive fashion. To test the generality of this "five-sites" rule, we have determined the partial amino acid sequences of red and green pigments from five mammalian orders (Artiodactyla, Carnivora, Lagomorpha, Perissodactyla, and Rodentia). The result suggests that cat (Felis catus), dog (Canis familiaris), and goat (Capra hircus) pigments all with AHYTA at the five critical sites have lambda max values of approximately 530 nm, whereas rat (Rattus norvegicus) pigment with AYYTS has a lambda max value of approximately 510 nm, which is accurately predicted by the five-sites rule. However, the observed lambda max values of the orthologous pigments of European rabbit (Oryctolagus cuniculus), white-tailed deer (Odocoileus virginianus), gray squirrel (Sciurus carolinensis), and guinea pig (Cavia procellus) are consistently more than 10 nm higher than the predicted values, suggesting the existence of additional molecular mechanisms for red and green color vision. The inferred amino acid sequences of ancestral organisms suggest that the extant mammalian red and green pigments appear to have evolved from a single ancestral green-red hybrid pigment by directed amino acid substitutions.     

Physiological compensation in antisense transformants: specific induction of an "ersatz" glucan endo-1,3-beta-glucosidase in plants infected with necrotizing viruses

Plant class I glucan endo-1,3-beta-glucosidases (beta-1,3-glucanase; 1,3-beta-D-glucan glucanohydrolase, EC 3.2.1.39) have been implicated in development and defense against pathogen attack. Nevertheless, beta-1,3-glucanase deficiencies generated by antisense transformation of Nicotiana sylvestris and tobacco have little biological effect. We report here that another beta-1,3-glucanase activity is induced in these deficient mutants after infection with necrotizing viruses. Induction of class I beta-1,3-glucanase was markedly inhibited in leaves of N. sylvestris and tobacco antisense transformants infected with tobacco necrosis virus and tobacco mosaic virus, respectively. A serologically distinct beta-1,3-glucanase activity was present in the infected antisense transformants but was absent in both healthy and infected control plants and in antisense transformants treated with the stress hormone ethylene. Immunoblot analyses, localization studies, and measurements of antibody specificity indicate that this compensatory beta-1,3-glucanase activity is an intracellular enzyme different from known tobacco beta-1,3-glucanases. Therefore, plants can compensate for a deficiency in enzyme activity by producing a functionally equivalent replacement--i.e., "ersatz"--protein or proteins. The fact that compensation for beta-1,3-glucanase activity occurs in response to infection argues strongly for an important role of these enzymes in pathogenesis.     

Ultrastructural evidence for an innervation of epithelial enterochromaffine cells in the guinea pig duodenum

The innervation of the duodenal enterochromaffine cells (E.C.) of the guinea pig was studied at the electronmicroscopic level. Pretreatment with 5-OH-dopamine was performed to visualize catecholaminergic (CA) nervous elements. Near the basement membrane of all examined E.C. in the crypts, bundles of unmyelinated nerve processes were observed, only partly ensheathed in a Schwann cell cover. At least 4 types of processes could be observed. 1) Boutons containing only small clear vesicles, probably cholinergic fibres; 2) boutons with small clear vesicles, and in addition large (greater than 200 nm) granules with a dense matrix (P-type-fibres); 3) boutons with small electron-dense vesicles, probably CA-fibres; and 4) processes with few vesicles but having the appearance of dendrites. No typical synaptic arrangements were observed, but the minimal distance between the E.C. and the nerve bundles was 150 to 250 nm, thus well within the functional limits of the "autonomic gap". Thus epithelial E.C. may be influenced by several types of nervous elements, including CA-fibres.     

Imported measles. A potential control problem

From Dec 23, 1978, through Jan 31, 1979, an outbreak of five laboratory-confirmed cases and four clinical cases of measles occurred in a Vietnamese refugee population living in a single housing complex in Albuquerque, NM. The index cases were in two refugee siblings in whom measles was incubating on arrival in the United States. Despite spread through three subsequent generations of disease transmission within the Vietnamese population, there was no additional spread into the general Albuquerque population. Responsible factors included the age distribution of susceptible persons, the social isolation of the refugee population, and the physical structure of the housing complex. There is a need to identify the problem of imported measles in "ethnic islands" in need of vaccination.     

Experimental electrocoagulation of dog esophageal and duodenal mucosa

The per review system for the assessment of research proposals is widely respected by working scientists. Nevertheless two problems associated with the operation of this system by the US National Institutes of Health are identified. First the scientist has no control over which committee will review an application and it may be considered by a quite inappropriate group. Second analysis of the committee composition suggests that in some of the groups several members are not active scientists and therefore not the "peers" of the applicant.     

The psychological development of orphanage-reared infants: interventions with outcomes (Tehran)

This paper describes five successive interventions in the rearing of infants at an orphanage in Tehran, with their outcomes. The outcomes were assessed longitudinally. The first of the successive groups, here called "waves", numbered 15. These Ss constitute the controls. The only intervention consisted of examining the infants every other week during the first year and every fourth week thereafter with the ordinal, sensorimotor scales of Uzgiris and Hunt. The audio-visual intervention intended for the second wave of 10 infants was tape-recorded mother talk and music under the control of the infants and mobiles that the infants could activate. This plan was never adequately implemented because of inadequate supervision. The third wave of 10 infants got extra untutored human care. The fourth wave of 20 infants got the kind of audio-visual intervention originally intended for the second wave plus access to responsive inanimate materials. For the fifth wave, numbering 11, the infant-caretaker ratio was reduced to two or three to one and the caretakers were taught the Badger program supplemented with procedures to foster vocal imitation and semantic mastery of body parts, clothing, toys, and other objects and events regularly encountered. The results show that each successive wave, excepting the second, achieved the top steps of nearly all seven of the ordinal scales at mean ages younger than the preceding wave, and the fifth wave surpassed even home-reared American children from predominantly professional families in achieving the top steps on five of the seven scales. The findings show that infants need not advance along all branches simultaneously and that the kinds of experience encountered determine the branch along which advancement occurs. A number of theoretical implications are examined. Especially important is the idea that a dependable educational psychology for infancy and early childhood calls for much more knowledge than we now have of the kinds of experience that advance development along each of the various branches.     

Vascular endothelial growth factor (VEGF) induces rapid prourokinase (pro-uPA) activation on the surface of endothelial cells

Vascular endothelial growth factor (VEGF) is the pivotal angiogenic growth factor activating endothelial cells to migrate, proliferate, and form capillary tubes. For an ordered endothelial cell migration, tissue invasion, and degradation of the extracellular matrix, proteolytic machinery is indispensable. Such machinery, suitable for localized proteolysis, is provided by the prourokinase-urokinase-plasmin system. Prourokinase (pro-uPA), the initial component of this system, is, however, synthesized in its inactive precursor form and as such bound to its cellular receptor uPAR. Here we identify a mechanism via which VEGF(165) interacting with its receptor VEGFR-2 rapidly induces prourokinase activation that is dependent on a change in integrin affinity, activation of matrix metalloproteinase 2 (MMP-2), and pro-uPA being bound to its surface receptor uPAR. This VEGF-induced pro-uPA activation on endothelial cells is responsible for VEGF-dependent local fibrinolytic activity and might be one of the initial steps in the angiogenic process.     

A cytosolic activity distinct from crm1 mediates nuclear export of protein kinase inhibitor in permeabilized cells

The leucine-rich nuclear export signal (NES) is used by a variety of proteins to facilitate their delivery from the nucleus to the cytoplasm. One of the best-studied examples, protein kinase inhibitor (PKI), binds to the catalytic subunit of protein kinase A in the nucleus and mediates its rapid export to the cytoplasm. We developed a permeabilized cell assay that reconstitutes nuclear export mediated by PKI, and we used it to characterize the cytosolic factors required for this process. The two-step assay involves an import phase and an export phase, and quantitation is achieved by digital fluorescence microscopy. During the import phase, a fluorescent derivative of streptavidin is imported into the nuclei of digitonin-permeabilized HeLa cells. During the export phase, biotinylated PKI diffuses into the nucleus, binds to fluorescent streptavidin, and mediates export of the complex to the cytoplasm. Nuclear export of the PKI complex is cytosol dependent and can be stimulated by addition of the purified NES receptor, Crm1. HeLa cell cytosol treated with N-ethylmaleimide (NEM) or phenyl-Sepharose to inactivate or deplete Crm1, respectively, is still fully active in the PKI export assay. Significantly, the export activity can be depleted from cytosol by preadsorption with a protein conjugate that contains a functional NES. These data indicate that cytosol contains an export activity that is distinct from Crm1 and is likely to correspond to an NES receptor.