Illicit drugs and anesthesia.

Substance abuse is the nation's number one health problem. With illicit drug use so prevalent, the anesthesia care team undoubtedly sees more people under the influence of illicit drugs. Cocaine, heroin, and marijuana are the drugs that are commonly used. Cocaine acts as an intense stimulant, heroin has profound sedative effects, and marijuana may cause various respiratory problems. Many times when drug users present for anesthesia, they will not admit to using illicit drugs, leaving the anesthetist to treat complications intraoperatively. This article discusses the history, street practices, pharmacodynamics, and anesthetic management of people using cocaine, heroin, and marijuana. This knowledge of how to treat patients abusing drugs will undoubtedly improve anesthetic outcomes. There are many illicit drugs used by people that anesthetists do not see frequently in the care of their patients, but the anesthetist should be aware of the common street drugs in use.

The left-right coordinator: the role of Vg1 in organizing left-right axis formation.

The asymmetries of internal organs are consistently oriented along the left-right axis in all vertebrates, and perturbations of left-right orientation lead to significant congenital disease. We propose a model in which a "left-right coordinator" interacts with the Spemann organizer to coordinate the evolutionarily conserved three-dimensional asymmetries in the embryo. The Vg1 cell-signaling pathway plays a central role in left-right coordinator function. Antagonists of Vg1 alter left-right development; antagonists of other members of the TGFbeta family do not. Cell-lineage directed expression of Vg1 protein can fully invert the left-right axis (situs inversus), can randomize left-right asymmetries, or can "rescue" a perturbed left-right axis in conjoined twins to normal orientation (situs solitus), indicating that Vg1 can mimic left-right coordinator activity. These are the first molecular manipulations in any vertebrate by which the left-right axis can be reliably controlled.

Initiation of vertebrate left-right axis formation by maternal Vg1.

In the development of the three-dimensional vertebrate body plan, the left-right axis is linked to the dorsoventral and anterioposterior axes. In humans, altered left-right development results in severe cardiovascular and visceral abnormalities in individuals and in conjoined twins. Although zygotically transcribed genes that are asymmetrically expressed have been identified, the mechanism by which left-right asymmetries are established during embryogenesis is unknown. Here we show that the Xenopus maternal gene Vg1, a member of the TGF-beta family of cell-signalling molecules which are implicated in dorsoanterior development, initiates left-right axis formation. Altered expression of Vg1 on the right side of 16-cell embryos or disruption of endogenous Vg1 signalling on the left side randomizes cardiac and visceral left-right orientation and alters expression of Xnr-1, a nodal-related molecular marker for left-right development. Furthermore, the orientation of the left-right axis in conjoined twins is dependent upon which cell-signalling molecule initiated twin formation and on whether the secondary axis is on the left or right side of the primary embryonic axis, implicating a molecular pathway leading to the formation of conjoined twins.

Relationship of N-arylacetamide metabolism and macromolecular binding to oncogenic transformation of C3H10T1/2CL8 cells.

The C3H10T1/2CL8 mouse embryo oncogenic transformation bioassay system detects a wide variety of chemical carcinogens. However, one carcinogen that does not transform C3H10T1/2CL8 cells is the liver carcinogen N-2-fluorenylacetamide (FAA). Previous reports indicate that an activated form of FAA, N-acetoxy-FAA (N-OAc-FAA), transforms these fibroblasts. In an effort to understand these results, the metabolism and binding to cellular macromolecules of FAA and N-OAc-FAA using C3H10T1/2CL8 cells was investigated. C3H10T1/2CL8 cells metabolized FAA to 7-hydroxy-FAA, 2-fluorenylamine and N-hydroxy-FAA (N-OH-FAA) at rates of 5.03, 2.22 and 3.33 pmol/h/10(6) cells, respectively. N-O-Ac-FAA was bound to the DNA and RNA in C3H10T1/2CL8 cells to the extent of 10.6 and 3.6 FAA residues/10(6) nucleotides, respectively, and to protein at 21.9 pmol FAA residues/mg protein. However, binding of FAA to DNA and RNA at similar concentrations to N-OAc-FAA was less than 0.3 and 0.6 residues/10(6) nucleotides, respectively. These results strongly indicate that the inability of FAA to transform C3H10T1/2CL8 cells residues in the cells' inability to metabolize it sufficiently to the proximate carcinogen N-OH-FAA and not an inherent insensitivity to its activated forms.

Identification of cocarcinogens and their potential mechanisms of action using C3H10T 1/2 CL8 mouse embryo fibroblasts.

The cocarcinogenic action of five agents which increase microsomal mixed-function oxidase activity in vivo was examined in the C3H10T 1/2 CL8 transformation assay. The compounds studied were benz(a)anthracene, 5,6-benzoflavone, phenobarbital, pregnenolone-16 alpha-carbonitrile, and Aroclor 1254. After a 48-hr pretreatment with the agent, the cells were then treated with benzo(a)pyrene [B(a)P] and the agent for an additional 24 hr. All agents except for Aroclor 1254 increased B(a)P-mediated transformation in C3H10T 1/2 CL8 cells. Benz(a)anthracene, 5,6-benzoflavone, phenobarbital, and pregnenolone-16 alpha-carbonitrile also increased the overall metabolism of B(a)P in C3H10T 1/2 CL8 cells to 9,10-dihydro-9,10-dihydroxybenzo(a)pyrene; 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene, 9-hydroxybenzo(a)pyrene, and 3-hydroxybenzo(a)pyrene. Growth studies indicated that all four agents had no stimulatory effect which might have explained the increases in transformation frequency. This suggests that these agents exert their cocarcinogenic action via increases in the enzyme-mediated pathways of B(a)P metabolism.