Silent and multiple mutations in p53 and the question of the hypermutability of tumors [published erratum appears in Carcinogenesis 1998 Jan;19(1):237]

Published data on TP53 mutations can be used to examine the question of whether generalized hypermutability is a necessary condition for tumorigenesis. Although individual mutations do play an etiologic role in tumor formation, the evidence so far does not make it necessary to assume a general mutability. Silent and multiple mutations in the TP53 data set indicate that a special hypermutability process operates on this gene during the generation of tumors. The percentage of silent p53 mutations observed (3%) is at least 20 times greater than would be expected and indicates hypermutability for this gene. The greater proportion of silent mutations among multiple p53 mutations (10%) indicates that the mutations occur nonselectively. The presence of silent mutations implies that not all mutations observed in tumors have an etiologic role. Analysis of the distribution of tumors with two, three, four and more p53 mutations suggests that mutations in some tumors occur in clusters possibly as a result of 'stuttering' in DNA synthesis. It is argued that the most likely alternative explanations of the data, polymorphism and/or a selective role for silent mutations, are not correct. It remains possible that the hypermutability process is restricted to particular genes or to regions of the genome as, for example, in antibody production. There is a surprising paucity of data on human polymorphism and nucleotide diversity which makes the analysis difficult.      

The conventional versus the new radiological contrast media. Cost-benefit analysis and medicolegal implications

New iodinated radiological contrast media, which are safer but much more expensive than the conventional ones, have been introduced. Since the financial implications are considerable a compromise between cost and safety is inevitable. It is therefore recommended that, at present, the conventional media be used routinely and the new media be reserved for potentially painful examinations and for patients at higher risk. Should a question of wrongfulness or negligence concerning the use of contrast media be considered by our courts, they will undoubtedly be influenced by what is considered 'common practice' and 'accepted practice' within a medical specialty and that may be co-determined by socio-economic considerations.     

L-arginine reverses the antinatriuretic effect of cyclosporin in renal transplant patients

BACKGROUND: Cyclosporin has been shown to facilitate renal vasoconstriction and to have an antinatriuretic effect. The existence of an interference of cyclosporin with the vasodilating properties of endothelium mediated by nitric oxide production could mediate these effects. On the other hand, the infusion of the nitric oxide precursor L-arginine has been shown to induce renal vasodilatation and to facilitate natriuresis in normal volunteers. We have investigated the renal effects of the administration of an infusion of L-arginine in renal transplant patients chronically treated with cyclosporin. To facilitate the analysis of the data the effects of the administration of a similar dose of cyclosporin on renal function during the infusion of a vehicle were also investigated during the administration of a vehicle of L-arginine. DESIGN: Ten male renal transplant patients, chronically treated with cyclosporin and with a stable renal function were studied during 2 consecutive days after the administration of the usual morning dose of cyclosporin. The first day they received an intravenous infusion of vehicle and the second the infusion of graded doses of L-arginine (50, 100, 150 mg/kg/h) during 3 consecutive h. RESULTS: The first day, after cyclosporin administration a significant fall (P < 0.01) was observed in natriuresis and kaliuresis in the absence of changes in renal plasma flow and glomerular filtration rate. After the administration of L-arginine significant (P < 0.01) increases of renal plasma flow, glomerular filtration rate, and natriuresis were seen. The increase in blood levels of cyclosporin after its administration did not differ between days 1 and 2. CONCLUSION: These results indicate that L-arginine facilitates renal vasodilatation and natriuresis in renal transplant patients. Furthermore, the observed increase in sodium excretion could indicate that L-arginine counteracts the antinatriuretic effect of cyclosporin.      

Psychological moods and subjectively perceived behavioral and somatic changes accompanying anabolic-androgenic steroid use.

To assess physiological and psychological states accompanying anabolic-androgenic steroid use, male weight lifters 1) were interviewed regarding their physical training and the patterns and effects of any drug use; 2) completed a written physical and medical history questionnaire, a Profile of Mood States questionnaire, and the Buss-Durkee Hostility Inventory; and 3) were physically examined, including a blood sample and urinalysis. Subjects were divided into current anabolic-androgenic steroid users (N = 12), previous users (N = 14), and nonusers (N = 24). Current and previous users reported the following changes associated with anabolic-androgenic steroid use: increases in enthusiasm, aggression, and irritability; changes in insomnia, muscle size, muscle strength and density; faster recovery from workouts and injuries; and changes in libido. We were unable to confirm these interview and physical and medical history questionnaire responses using standardized and well-accepted psychological inventories. There were no significant differences among groups for any Profile of Moods factor, total mood disturbance, total Buss-Durkee Hostility Inventory score, or any subscale. For current users, there were no significant correlations between either total weekly drug dose or length of time on the current cycle of anabolic-androgenic steroids and any individual scale of the Profile of Mood States, Buss-Durkee Hostility Inventory, Profile of Mood States total mood disturbance, or composite Buss-Durkee Hostility Inventory score. Furthermore, anabolic-androgenic steroid users did not differ in their responses on these inventories from nonusers or from general population norms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Meniscal abnormalities: prospective correlation of double-contrast arthrography and arthroscopy

In a prospective study conducted over a 12-month period, 30 patients underwent double-contrast arthrography of the knee followed by arthroscopic study. An 80% correlation rate was found between results. Arthrography had a higher rate of accuracy (93%) than arthroscopy (84%) and had a 7% false-positive and 0% false-negative rate. A commonly overlooked arthrographic sign--the triple-S or stuck sail sign--was 91% accurate in the prediction of meniscal tears. The complementary nature of the two examinations is discussed.     

The insulin-like growth factor, somatomedin-C, modulates low density lipoprotein metabolism by swine granulosa cells

Insulin-like growth factor I (IGF-I) synergistically amplified the stimulatory effect of low density lipoprotein (LDL) on progesterone biosynthesis by primary cultures of swine ovarian cells. The mechanisms subserving this facilitative interaction included the following. IGF-I's synergism with LDL was associated with a decrease in the mean half-maximally stimulatory concentration of LDL from 20-3.5 micrograms/ml. IGF-I increased by 3- to 6-fold the number of specific high affinity LDL receptors on ovarian cells, with no change in apparent binding affinity. IGF-I augmented by 3- and 18-fold the maximal rates of [125I]iodo-LDL internalization and degradation, respectively, without altering half-maximally effective concentrations of LDL supporting these processes. IGF-I increased by 2- to 2.5-fold the total mass of free and esterified cholesterol contained in granulosa cells. IGF-I stimulated the intracellular accumulation of free [3H]cholesterol and [3H]cholesteryl ester from exogenous [3H]cholesteryl linoleate-labeled LDL, and amplified [3H]progesterone secretion by granulosa cells exposed to this source of lipoprotein-borne sterol. These actions of IGF-I were demonstrated at 30- to 100-fold lower concentrations of IGF-I than insulin. We conclude that IGF-I and LDL synergistically enhance progesterone biosynthesis by ovarian cells. This synergism occurs in part via mechanisms that regulate the effectual delivery of lipoprotein-borne cholesterol substrate into cellular sterol pools that participate in steroid hormone biosynthesis.