PTCH codon 1315 polymorphism and risk for nonmelanoma skin cancer.

BACKGROUND: The PTCH tumour suppressor gene is involved in the development of nearly all basal cell carcinomas (BCCs) of the skin and a fraction of squamous cell carcinomas (SCCs). A nonconservative Pro/Leu nucleotide polymorphism within PTCH exon 23 at codon 1315 was recently reported to be potentially important for the development of breast epithelial cell cancers. Objectives Accordingly, the status of PTCH codon 1315 was analysed for a possible association with the development of nonmelanoma skin cancers (NMSCs) in a pilot study. Because skin cancer risk is affected by specific population-dependent phenotypes such as skin and hair colour, codon 1315 was also analysed for normal allele frequency variation in human populations having differing extents of eumelanin vs. phaeomelanin. METHODS: The single nucleotide polymorphism in codon 1315 of the human PTCH gene was analysed in genomic DNA from six different populations comprising 472 blood samples and from 170 patients in four different categories with NMSC. Polymerase chain reaction and pyrosequencing were used to determine the allele frequencies. Allelic loss was furthermore determined in tumours following microdissection. RESULTS: The Pro/Pro genotype frequency ranged from 30% to 65% between populations, with a significant trend for a reduced frequency of the Pro/Pro genotype in populations having lighter pigmentation (P = 0.020). Pro/Pro frequency showed an increasing trend with increasing tumour case severity (P = 0.027). In 260 samples from 180 Swedish patients with NMSC and a control group of 96 healthy ethnically matched volunteers, no statistically significant pairwise differences between groups were detected in the PTCH codon 1315 allelic distribution, neither was a difference seen for multiple or early onset cases of BCC in the Swedish population. In Swedish patients with single tumours, allelic loss (loss of heterozygosity) was observed in 20 of 30 (67%) patients with BCC and four of 22 (18%) patients with SCC, with no preference in the allele lost. In contrast, the Pro/Pro genotype was frequent in seven U.S. patients having multiple independent BCCs. One of these patients was heterozygous, enabling allelic loss studies. Of 20 independent tumours, 11 had lost an allele; 10 of the 11 had lost Leu, suggesting nonrandom loss that favoured retention of Pro (P = 0.0059). CONCLUSIONS: Our results indicate an association between the eumelanin-to-phaeomelanin shift and a shift from the Pro/Pro genotype to Leu-containing genotypes. Failure to lose Pro during the shift to phaeomelanin may be associated with an increased population risk for BCC and increased individual risk for multiple BCC. During development of a tumour, the effect of Pro may be magnified by loss of the Leu allele.

Correlational cuing as a function of target complexity and target-flanker similarity.

It is generally assumed that the correlational cuing effect (CE) between targets and correlated flankers is due to learning association between the flankers and their correlated responses. The present study challenges this view. Experiment 1 shows that the CE for targets composed of color is eliminated as soon as the correlation is removed. Experiment 2 shows that the CE during training is not due to association of the flankers with responses. Experiment 3 shows that at least some of the CE during training with the correlation is due to repetition priming of the display. Experiment 4 replicates the results of Experiment 1 for orientation targets. In Experiments 5-7, more typical tasks with letter targets are examined, and it is demonstrated that preexperimental similarity between targets and correlated flankers is crucial. The CE for correlated but dissimilar target-flanker pairs, similar to that for color and orientation targets, is confined to on-line processes that occur during training. The CE is transferred, however, for correlated and similar target-flanker pairs. We propose that, at least for the simple stimulus to response mapping used in our study, the CE is not due to learning at all. Instead it is due to (1) on-line processes, such as repetition priming, that occur during training with the correlation and (2) a regular flanker effect (see, e.g., B. A. Eriksen & C. W. Eriksen, 1974) that occurs for similar target-flanker pairs.

New insights into the regulation of parathyroid hormone synthesis and secretion in chronic renal failure.

The main factors which regulate parathyroid hormone (PTH) production are calcium, phosphate, vitamin D and the sex steroids, estrogens and progestagins. Hypocalcaemia leads to increased PTH secretion in seconds and minutes, gene expression in hours and parathyroid cell number in weeks and months. Hypercalcaemia leads to a decrease in PTH secretion by its action on the parathyroid cell calcium receptor and no decrease in PTH mRNA concentrations. There is now convincing evidence that phosphate regulates the parathyroids independent of its effect on serum calcium and 1,25-dihydroxyvitamin D3. (1,25(OH)2D3). In vivo in rats hypophosphataemia markedly decreases PTH mRNA and serum PTH independent of its effect on serum calcium and 1,25(OH)2D3. Clinical studies also indicate that phosphate regulates the parathyroids independent of its effect on serum calcium and 1,25(OH)2D3 1,25(OH)2D3 itself has a marked effect on the parathyroids where it decreases PTH gene transcription by a direct action. Parathyroid cell proliferation is regulated by dietary calcium and phosphate with hypocalcaemia markedly increasing and hypophosphataemia markedly decreasing the number of proliferating cells. The application of basic science findings of how calcium, phosphate and 1,25(OH)2D3 regulate the parathyroids has led to an efficient and safe prescription for the management of the secondary hyperparathyroidism of chronic renal failure which is the maintenance of a normal serum calcium and phosphate and the careful use of bolus doses of 1,25(OH)2D3.

Adoption of thermometry into clinical practice in the United States.

Technologic advances in thermometer design and conceptual advances in the understanding of homeostasis between 1700 and 1850 led to recognition of the usefulness of measuring body temperature in human disease. These advances took place in Europe and Great Britain, culminating in the publication in 1868 of the seminal work on fever in human disease by Carl Wunderlich. In the United States thermometry was popularized by a number of distinguished American physicians who used European data that had appeared in British and American journals even before 1868. Thus Edward Seguin and Austin Flint included fever curves and vital signs in articles that appeared in 1866. Flint and Jacob DaCosta added sections on thermometry to their medical textbooks in 1866-1867, and Edouard Seguin (the father of Edward) encouraged the use of thermometry by the public at large in a series of articles in the medical and lay press. Within just two decades thermometry became recognized as an indispensable medical tool, which it remains to the present time.

Leukocyte adherence inhibition assay in the diagnosis and follow-up of colorectal cancer patients.

Antitumor immune response to colorectal cancer extract was tested by the tube leukocyte adherence inhibition (LAI) assay. Of 70 colorectal cancer patients, 38 (54%) were LAI-positive. In contrast, 15 of 159 (9%) healthy individuals and 2 of 28 (7%) patients with nonmalignant diseases were positive. The LAI activity disappeared a few months after surgery and remained negative in patients with no evidence of disease as well as in patients with disseminated progressed disease. A change of LAI from negative to positive during the follow up period correlated in some cases with the recurrence of the disease, but was observed also in cases with no clinical evidence of disease.

Differences in learning and extinction in response to vasopressin in six inbred mouse strains.

Vasopressin was found to enhance acquisition of conditioned avoidance responses in one inbred mouse strain and to retard extinction; in another inbred mouse strain vasopressin depressed the acquisition of conditioned avoidance; in four additional inbred mouse strains vasopressin had no effect on conditioned avoidance learning.