New insights on commemoration of the dead through mortuary and architectural use of pigments at Neolithic Çatalhöyük, Turkey.

The cultural use of pigments in human societies is associated with ritual activities and the creation of social memory. Neolithic Çatalhöyük (Turkey, 7100-5950 cal BC) provides a unique case study for the exploration of links between pigments in burials, demographic data and colourants in contemporary architectural contexts. This study presents the first combined analysis of funerary and architectural evidence of pigment use in Neolithic Anatolia and discusses the possible social processes underlying the observed statistical patterns. Results reveal that pigments were either applied directly to the deceased or included in the grave as a burial association. The most commonly used pigment was red ochre. Cinnabar was mainly applied to males and blue/green pigment was associated with females. A correlation was found between the number of buried individuals and the number of painted layers in the buildings. Mortuary practices seem to have followed specific selection processes independent of sex and age-at-death of the deceased. This study offers new insights about the social factors involved in pigment use in this community, and contributes to the interpretation of funerary practices in Neolithic Anatolia. Specifically, it suggests that visual expression, ritual performance and symbolic associations were elements of shared long-term socio-cultural practices.

Expression of simple epithelial cytokeratins in mouse epidermal keratinocytes harboring Harvey ras gene alterations.

Activation of a Harvey ras (H-ras) protooncogene is a frequent event associated with mouse epidermal carcinogenesis. We report that the transfection of a human H-ras oncogene into an immortalized mouse epidermal cell line (MCA3D) induces the anomalous expression of cytokeratins (CKs) 8 and 18 characteristic of simple epithelia. The comparison of various transfectant cell clones indicated a direct correlation between the levels of CK8 expression and the mutated H-ras p21s. The expression of simple epithelial CKs is also described in cell lines derived from mouse skin carcinomas (HaCa4, CarC) and in keratinocytes transformed in vitro by a chemical carcinogen (PDV, PDVC57), all of which contain altered H-ras genes. The induction of CK8 and CK18 occurs at the mRNA level and, although both CK8 and CK18 mRNAs are expressed, CK18 protein does not accumulate whereas CK8 is incorporated into intermediate filaments. Immunofluorescence studies show that the pattern of CK8 protein expression is heterogeneous; some cells express very low amounts of CK8, whereas others synthesize relatively high levels of this protein. However, selection of strongly CK8-positive cells was found in one case where a more malignant population of cells (PDVC57) was derived by tumor transplantation of PDV. Our results suggest that activation of a H-ras gene can alter the normal differentiation program of epidermal cells and that the ability to synthesize CK8 and CK18 could be related to tumor progression.

Loss of growth control by TGF-beta occurs at a late stage of mouse skin carcinogenesis and is independent of ras gene activation.

The relationship between the expression of a mutant ras gene in epithelial cells and loss of responsiveness to the negative effects of transforming growth factor beta (TGF-beta) is presently unclear. We have investigated this question using a series of cell lines derived from benign and malignant mouse skin tumours which express mutant forms of the H-ras gene. Immortalised, non-tumorigenic mouse epidermal cells respond to TGF-beta by cessation of growth, whereas in a series of malignant carcinoma lines the response was substantially reduced. Introduction of a mutant H-ras gene into the immortalised cells did not lead to any appreciable change in TGF-beta responsiveness, suggesting that initiation of carcinogenesis by ras mutation does not directly alter growth control by this pathway. Of two non-tumorigenic papilloma lines tested which had mutant H-ras genes, one retained complete sensitivity to TGF-beta, whereas the other showed a similar response to carcinomas. We conclude that growth control by TGF-beta is lost at a relatively late stage of carcinogenesis in this system, and is independent of ras gene activation.

Transformation of mouse skin endothelial cells in vivo by direct application of plasmid DNA encoding the human T24 H-ras oncogene.

Plasmid DNA containing the human T24 H-ras oncogene, with or without viral transcriptional enhancer sequences, was applied to scarified mouse skin, followed by multiple treatments with the tumour promoter 12-O-tetradecanoyl-phorbol-13-acetate. This resulted in the formation of vasoformative tumours histologically characterized as lymphangiosarcomas. All of the animals treated developed cystic fluid-filled swellings. Polymerase chain reaction analysis revealed the presence of human H-ras sequences within the cystic fluid from 3 out of 4 swellings. An endothelial cell line established from the cystic fluid removed from one of these swellings was found to contain human H-ras sequences and to express the mutant human p21ras. Injection of the cell line into nude mice, or adult syngeneic mice, resulted in the formation of aggressive angiosarcomas. Further experiments showed that 12-O-tetradecanol-phorbol-13-acetate promotion is not required for tumour formation and would appear to reduce the yield of tumours. These results indicate that a single application of the human H-ras oncogene is sufficient to induce endothelial cell transformation in vivo, even in the absence of any further promotional stimulus.

Predictors of preclinical and clinical performance of minority medical students.

Although several studies have examined the relationship between minority students' admissions profiles and performance in the preclinical curriculum, there is a dearth of information about the ability of admissions variables to predict performance in the clerkships and on National Boards, Part II. Consistent with other research, a study of 59 minority students at the Albert Einstein College of Medicine found that the Medical College Aptitude Test (MCAT) chemistry score is the most consistent predictor of performance on internal examinations in years 1 and 2, and on National Boards, Part I. On the Part II examination, however, the only significant correlation is with the MCAT reading score, while the MCAT quantitative score and the recommendation of the premedical advisor are the best predictors of clerkship grades. Since students' mean MCATs and grade point averages (GPAs) are similar to those of all minority students accepted to medical schools in 1982, these findings may be generalized to that larger population.

The practice of general internal medicine by subspecialists.

To determine the proportion of specialists in internal medicine at a university medical center practicing general internal medicine in addition to their specialty, full-time and voluntary faculty were asked to complete a questionnaire concerning their practice patterns. In addition, the directories of two of the largest managed-care groups in the area were reviewed to identify physicians who were also faculty members, to determine whether faculty in these directories self-identified as general internists. Excluding those with primary research appointments, 303 faculty in the Department of Medicine were asked to participate. Of these, 187 (62%) responded, of whom 86 (46%) were full-time and 101 (54%) voluntary faculty. Of the respondents, 183 (98%) were either board certified (152; 81%) or board eligible (31; 17%) in a subspecialty. Both general internal medicine and specialty medicine were practiced by 116 (65%), with full-time faculty being more likely to have solely subspecialty practices (P < .001). The majority of faculty (150; 80%) participated in managed care. A review of directories of two managed-care groups revealed that 100 (87%) of the 115 faculty with appointments within subspecialty divisions of the Department of Medicine were listed as general internists. Subspecialists in internal medicine already spend considerable time practicing general medicine and are increasingly willing to identify themselves as generalists. Unless this is recognized, the future need for generalists may be overestimated considerably.

Comparison of ras activation during epidermal carcinogenesis in vitro and in vivo.

Mouse epidermal cells have frequently been used to study the role of ras oncogenes in transformation in vivo and in vitro. After initiation with dimethylbenzanthracene (DMBA) in vivo, greater than 90% of the papillomas arising show the same A:T----T:A transversion at codon 61 of the H-ras gene, presumed to be the initiating event. On the other hand, initiation of epidermal cells in culture with carcinogens, followed by selection of initiated cells by resistance to calcium-induced differentiation, does not in general lead to the isolation of clones carrying mutant ras genes. Some other aspects of tumour progression in vivo can be reproduced using epidermal cells in culture: a rare DMBA transformant carrying the codon 61 mutation and expressing a 2:1 ratio of normal to mutant ras alleles gave rise upon transplantation to a more aggressive line in which the ratio of normal to mutant H-ras genes (and p21 products) was reversed. Similar alterations in ras gene dosage have been seen during progression of papillomas to carcinomas in vivo. We conclude that the mechanisms of initiation in vitro may differ substantially from in vivo, and depend on the particular culture conditions used. Moreover, the effects of mutant H-ras expression in mouse epidermal cells are variable depending on the genetic background of the cell.

Molecular mechanisms of invasion and metastasis during mouse skin tumour progression.

The ultimate stage of carcinogenesis in both human and mouse epithelial cells is the ability to invade surrounding tissues and metastasize to distant sites. In mouse skin tumours, the development of the invasive, spindle cell phenotype is associated with an imbalance of alleles on mouse chromosome 7, including the H-ras gene. In previous work, we have described clonally related squamous and spindle cell lines from the same primary tumour which differed substantially in morphology and behaviour, but showed the same series of mutations in H-ras and p53 genes. One of the events which takes place during this transition is disruption of cell-cell contacts, possibly due to the induced expression of metalloproteinases such as stromelysin-1 and disappearance of the cell adhesion molecule E-cadherin. Parallel studies using somatic cell hybrids have shown that the spindle cell phenotype is recessive in hybrids between squamous and spindle cells. We propose that an important epidermal differentiation-controlling gene is lost during the spindle cell transition.