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Mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane, (o,p'-DDD)] is the only drug approved for the treatment for adrenocortical carcinoma (ACC) and has also been used for various forms of glucocorticoid excess. Through still largely unknown mechanisms, mitotane inhibits adrenal steroid synthesis and adrenocortical cell proliferation. Mitotane increases hepatic metabolism of cortisol, and an increased replacement dose of glucocorticoids is standard of care during mitotane treatment. Recently, sunitinib, a multityrosine kinase inhibitor (TKI), has been found to be rapidly metabolized by CYP3A4 during mitotane treatment, indicating clinically relevant drug interactions with mitotane. We here summarize the current evidence concerning mitotane-induced changes in hepatic monooxygenase expression, list drugs potentially affected by mitotane-related CYP3A4 induction and suggest alternatives. For example, using standard doses of macrolide antibiotics is unlikely to reach sufficient plasma levels, making fluoroquinolones in many cases a superior choice. Similarly, statins such as simvastatin are metabolized by CYP3A4, whereas others like pravastatin are not. Importantly, in the past, several clinical trials using cytotoxic drugs but also targeted therapies in ACC yielded disappointing results. This lack of antineoplastic activity may be explained in part by insufficient drug exposure owing to enhanced drug metabolism induced by mitotane. Thus, induction of CYP3A4 by mitotane needs to be considered in the design of future clinical trials in ACC.

The present account spans the history of arginine regulation from its discovery in 1955 until the present. In 1957 I demonstrated that not only added arginine but also internally produced arginine represses enzyme formation and that the potential for enzyme synthesis is in excess of what is required for growth. In 1959 I located the regulatory gene argR encoding the arginine repressor. An unusual feature of this research was the finding that in E. coli B, in contrast to E. coli K12, arginine synthesis is permanently repressed, independent of arginine. This was due to a single amino acid difference between the two repressors. Recent studies showed that, in natural populations of E. coli, K12-type regulation is much more frequent than B-type regulation, and that E. coli B evolved from a strain with K12-type regulation. In competition experiments, E. coli K12 was found to be favored in the presence of arginine and E. coli B in its absence, showing that contrary to expectations permanently turned off regulation is favored over negative regulation in some environments.

Der Wirtschaftsverlauf ist erstmals naturwissenschaftlich mit einem einfachen Teststreifen exakt vorhersagbar. Dieser Indikator und erkenntnispraktische Fortschritte starken den Chemiestandort nachhaltig.

The course of vinyl chloride-induced disease observed in 21 polyvinyl chloride (PVC) production workers, covering the period from first exposure to diagnosis and finally to death, and the difficulties in elucidating the true character of the lesions and their occupational origin are described. In 19 cases death was due to malignant hepatoma, predominantly angiosarcoma of the liver, but hepatocellular and cholangiocellular carcinoma were also found. Two workers died of complications of noncirrhotic portal fibrosis with portal hypertension. Except for the final stages, there was strikingly little impairment of hepatic function. Latency periods in workers with malignant hepatoma ranged from 12 to 34 years; mean latency was 22 years, and younger age at first exposure (here age < 27) seemed to have been accompanied by shorter latency periods.

Retrons are genetic elements that encode multicopy single-stranded DNAs called msDNAs. They are clonally distributed in Escherichia coli and retrons in different clones produce DNAs with different nucleotide sequences. msDNAs consist of an RNA molecule covalently linked to a single-stranded DNA molecule. The latter contains an inverted repeat, resulting in a stem-loop structure. In two retrons, Ec83 and Ec78, the DNA is cleaved off from the RNA. All known retrons except Ec78, have one or more mismatched base pairs in the stem-loop structure. We found that two retrons, Ec86 and Ec83, when present in high copy numbers are mutagenic. The ratios of mutation frequencies observed in Lac- indicator strains were similar to the ratios observed for a mutant defective in mismatch repair. It is known that some proteins required for mismatch repair bind to mismatched base pairs prior to carrying out repair. The similarity in the mutation frequency ratios suggested that the mutagenesis caused by msDNAs of retrons Ec86 and Ec83 might be due to sequestration of a mismatch repair protein by msDNA. Strong support for this interpretation was obtained from the finding that the msDNA produced by retron Ec78 is not mutagenic.

Summary Arginine biosynthesis in Escherichia coli is negatively regulated by a hexameric repressor protein, encoded by the gene argR and the corepressor arginine. By hydroxylamine mutagenesis two types of argR mutants were isolated and mapped. The first type is transdominant. In heterodiploids, these mutant polypeptides reduce the activity of the wild-type repressor, presumably by forming heteropolymers. Four mutant repressor proteins were purified. Two of these map in the N-terminal half of the protein. Gel retardation experiments showed that they bind poorly to DNA, but they could be precipitated by l-arginine at the same concentration as the wild-type repressor. The other two mutant repressors map in the C-terminal half of the protein. They are poorly precipitated by L-arginine and they bind poorly to DNA. In addition, one of these mutants appears to exist as a dimer. The second type of argR mutant repressor consists of super-repressors. Such mutants behave as arginine auxotrophs as a result of hyper-repression of arginine biosynthetic enzymes. They map at many locations throughout the argR gene. Three arginine super-repressor proteins were purified, in comparison with the wild-type repressor, two of them were shown to have a higher DNA-binding affinity in the absence of bound arginine, while the third was shown to have a higher DNA-binding affinity when bound to arginine.

This paper is a selective review of the methods, problems, and findings in the area of operant stimulus generalization over the 25 years since the publication of the original paper by Guttman and Kalish (1956) on discriminability and spectral generalization in the pigeon. The paper falls into five main sections, which encompass the main themes and problems stemming from the Guttman and Kalish work and its immediate successors. The first section addresses the relationship between stimulus generalization and stimulus control, as well as the variety of testing procedures and dependent variables used to measure generalization. The next section reviews the limited literature on the effects of early rearing on the generalization gradient. The relationship between discriminability among test stimuli and the slope of the spectral gradient is discussed in the third section, with emphasis upon recent reassessments of the pigeon's hue discriminability function. The fourth section reviews the topic of inhibitory stimulus control, one which developed with the discovery of the peak shift following intradimensional discrimination training. Problems of definition and measurement are discussed in conjunction with the gradient forms used to index inhibitory control. The last section is devoted to attentional effects and the two principal theories postulated to account for them. A survey of different attentional paradigms is provided and the possible role of constant irrelevant stimuli as a source of control is examined. A brief conclusion summarizes the contribution of the generalization technique toward an understanding of the nature and acquisition of stimulus control.

A number of peptide-ester substrates of the general structure Ac-Lxn-...-Lx2-Lx1-OMe have been synthesized and their alpha-chymotrypsin-catalyzed hydrolysis studied. The kinetic analysis involved varying the concentration of substrate and methanol product, and measuring rates along the entire progression curve. For the dipeptide esters Ac-Lx2-Lx1-OMe and the amino-acid derivatives Ac-Lx1-OMe the following constants could be determined: the dissociation constant of the enzyme-substrate complex, KEA, both rate constants of the acylation step, k23 and k32, and the forward rate constant of the deacylation step, k31. For the tripeptide ester Ac-Ala-Ala-Tyr-OMe it appears that the rate constant for the dissociation of the enzyme-substrate complex, k21, is smaller than the rate constant for acylation, k23. Thus, for this substrate only the association and dissociation rate constants k12 and k21 could be determined and the values of k23, k32 and k31 only indirectly estimated. The influence of structural changes in the peptide moiety of the substrates on reactivity has been established by comparing the rate constants of appropriate pairs of substrates. It was found that the substrate reactivity, as measured by k23/KEA, increase with the number and strength of the secondary interactions in a manner consistent with the binding scheme which has been proposed on the basis of crystallographic studies. The effect of a particular interaction on k23 and on KEA is dependent on the nature of the other interactions. However, the effect of k23/KEA appears to be independent of the presence of the other interactions and therefore characteristic of that particular interaction. The results for these substrates are compared with those found previously for a series of peptide substrates of the structure Ac-Lxn-... Lx2-...-Lx1-Gly-NH2 which have the same acyl moiety as the peptide esters studied in this work.

The sand in the Alexandria coastal dunefield is derived from the sandy beach which forms the seaward boundary of the dunefield. Sand is blown off the beach onto the dunefield by the high-energy onshore-directed dominant wind. The dunefield has been forming over the past 6500 years. Sand transport rates calculated from dune movement rates and wind data range from 15 to 30 m3 m -1 yr-1 in an ENE direction. The sand transport rate decreases with increasing distance from the sea due to a reduction in wind speed resulting from the higher drag imposed upon the wind by the land surface. Aeolian sand movement rates of this order are typical of dunefields around the world. The total volume of sand blown into the dunefield is 375 000 m3 yr-1. Sand is being lost to the sea by wave erosion along the eastern third of the dunefield at a rate of 45 000 m3 yr -1. The dunefield thus gains 330 000 m3 of sand per year. This results in dunefield growth by vertical accretion at about 1.5 mm yr-1 and landward movement at about 0.25 m yr-1. The dunefield is a significant sand sink in the coastal sand transport system. The rate of deposition in coastal dunefields can be 10 times as high as rates of deposition in continental sand seas. The higher rate of deposition may result from the abundant sand supply on sandy beaches, and the higher energy of coastal winds. Wind transport is slow and steady compared to fluvial or longshore drift transport of sediment, and catastrophic aeolian events do not seem to be significant in wind-laid deposits.

—The damaging effect of visible light on photoreceptors and pigment epithelium has been studied mainly in the albino rat with continuous or intermittent exposures to green light for up to several days. Similar damage as in the albino rat but with different doses of light and different times of exposures were observed in pigmented rats, hamster strains, mouse strains and in the nocturnal monkey. The damage is graded histologically mainly by the size of the area of the retina over which the photoreceptors have died. The damage is quantitatively assessed by the measurement of ERG and DNA content of the retina. The action spectrum for the irreversible damage agress with the absorption curve for rhodopsin. Threshold damage occurs with diffuse light that reduces acutely the rhodopsin of the whole retina by about 10%. Damage is a function of body and eye temperature during exposure. At a body temperature of 42°, 2–4 h of exposure produces the same damage as exposure for 30 h at normal temperature using 1500 lux. The damage is also very markedly dependent upon the light history of the animal prior to exposure. Cyclic environmental light of I to 10 ft-cd for several days or weeks reduces very significantly the damaging effect compared to animals reared simultaneously in continuous darkness. Cyclic light rearing is associated with a reduction in opsin and rhodopsin of the whole retina, an increase in the molar phospholipid/opsin ratio and a reduction in the length of the outer segment. Protection is also produced by Vitamin A deficiency but significantly only when rhodopsin content is decreased by maintenance in very weak cyclic light. Thus Vitamin A deficiency and environmental light seem to use the same mechanism. Results do not support the possibility that damage is caused by a cytotoxic effect of retinol.

Reverse transcriptase, discovered in 1970 in retroviruses, has until recently been found only in eukaryotic organisms. Recently it was shown to occur in two groups of bacteria: myxobacteria and Escherichia coli. The gene for reverse transcriptase is part of a chromosomal genetic element that codes for the production of a branched DNA-RNA compound. In this compound a single-stranded DNA is connected to RNA at a specific G residue by a 2'-5' phosphodiester linkage. The precursor for the DNA-RNA compound is a folded messenger RNA, in which the specific G residue is the initiation point for reverse transcription. In the final DNA-RNA compound, the portion of the RNA transcribed by reverse transcriptase is eliminated by RNase H. The DNA-RNA compound is present in several hundred copies per cell. Its biological function is unknown at present.