A conundrum in molecular toxicology: molecular and biological changes during neoplastic transformation of human cells

The process of multistage carcinogenesis lends itself to the concept that the effects of carcinogens are mediated through dose-related, multi-hit, linear changes. Multiple in vitro model systems have been developed that are designed to examine the cellular changes associated with the progression of cells through the different stages in the process; however, these systems may have inherent limitations due to the cell lines used for these studies, the manner of assessing the effects of the carcinogens, and the subsequent growth and differentiation of the exposed cells. Each of these variables results in increasing levels of uncertainty relative to the correlation of the events with the actual process of human tumor development. Therefore, the prediction of the ultimate effect of any carcinogen is difficult. Moreover, relationships between individual biological endpoints resulting from carcinogen treatment appear at best to be approximations. The presence of an activated carcinogen inside the cell can give rise to multiple outcomes, only some of which may be critical events. For example, site-specific modification of the 12th and 13th codons of H-ras is different than that in the adjacent 14th and 15th codons. It is interesting to speculate what effect these differences might have on a biological outcome, e.g., transformation to anchorage-independent growth. The use of different model systems to examine the effects of activated carcinogens also creates additional problems. Comparisons of in vitro transformed cells with similar cells isolated from human tumors indicate that the culture environment appears to influence the expression of a particular phenotype, in that human tumor cells in culture express many of the same parameters as those found in cells transformed with carcinogens in vitro. If the process of transformation is linear, then less aggressive phenotypes should progress to a more aggressive transformed stage. However, in carcinogen-transformed human cells, the populations exhibit phenotypic diversity in that many of the transformed cells differentiate and fail to continue to divide in culture. Historically, we have assumed only a limited role for epigenetic modulation of molecular changes that occur during progression; however, our data suggest quite strongly that nonmalignant tumor populations can be converted to a more malignant phenotype without additional mutations taking place and, conversely, malignant populations can be downregulated to a nontumorigenic phenotype. Tumor cell plasticity is not only a fundamental characteristic of diverse types of human tumors, but also appears as an integral characteristic of carcinogen-transformed cells in vitro.     

Practical guidelines for the assessment and treatment of selective mutism

OBJECTIVE: To provide practical guidelines for the assessment and treatment of children with selective mutism, in light of the recent hypothesis that selective mutism might be best conceptualized as a childhood anxiety disorder. METHOD: An extensive literature review was completed on the phenomenology, evaluation, and treatment of children with selective mutism. Additional recommendations were based on clinical experience from the authors' selective mutism clinic. RESULTS: No systematic studies of the phenomenology of children with selective mutism were found. Reports described diverse and primarily noncontrolled treatment approaches with minimal follow-up information. Assessment and treatment options for selective mutism are presented, based on new hypotheses that focus on the anxiety component of this disorder. Ongoing research suggests a role for behavior modification and pharmacotherapy similar to the approaches used for adults with social phobia. CONCLUSION: Selectively mute children deserve a comprehensive evaluation to identify primary and comorbid problems that might require treatment. A school-based multidisciplinary individualized treatment plan is recommended, involving the combined effort of teachers, clinicians, and parents with home- and clinic-based interventions (individual and family psychotherapy, pharmacotherapy) as required.     

Renal function tests for windows--a model for the development and distribution of medical software on the Internet

In the present study, pharyngeal size was investigated on the lateral cephalometric head films of 90 subjects, 45 males and 45 females, having different ANB angles. All of the subjects were aged 13 to 15 years. The films were taken at natural head position, and all were divided into three groups according to the ANB angle: ANB angles smaller than 1 degree, between 1 degree and 5 degrees, and larger than 5 degrees. In addition, each group was also divided into two subgroups according to sex. The effects of the ANB angle and sex on the pharyngeal size were investigated by means of variance analysis. It has been observed that two measurements, hy-apw4 and oropharynx area measurements, were affected by the change of ANB angle, and two other measurements, t-ppw and hy-apw2 measurements, by the sex; and that hy-apw4 measurement and oropharynx area became smaller with the increase of ANB angle.     

Pharmacokinetics of tablet huperzine A in six volunteers

AIM: To study pharmacokinetics of tablet huperzine A (Hup-A) in Chinese volunteers to help establishing its drug administration schedule. METHODS: For 6 volunteers after a single oral dose of 0.99 mg, drug concentrations in plasma were assayed by reverse phase high pressure liquid chromatography (HPLC) at 0.5, 0.75, 1.0, 1.25, 1.5, 2, 4, 6, 8, and 10 h. The pharmacokinetic parameters were calculated with a 3P87 program by computer. RESULTS: The time course of plasma concentrations conformed to a one-compartment open model with a first order absorption. The pharmacokinetic parameters were as follows: T 1/2ka = 12.6 min, T 1/2ke = 288.5 min, Tmax = 79.6 min, Cmax = 8.4 micrograms L-1, AUC = 4.1 mg L-1 min. CONCLUSION: Hup-A was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate.     

Test-retest reliability of high-frequency thresholds at bedside with sensorineural hearing-impaired listeners

Previous investigations have established the reliability of high-frequency thresholds performed in a sound suite using headphones. In addition, test-retest reliability of high-frequency thresholds in adults with normal hearing in a hospital room versus a sound-treated booth has also been established. The current study evaluated the test-retest reliability of thresholds in the 8000- to 18000-Hz range in 15 hearing-impaired adults (26 ears) with varying degrees of sensorineural hearing loss. A high-frequency audiometer and supra-aural earphones were used to measure thresholds in a typical hospital room. Results revealed no significant difference between repeated threshold measures. This study represents the third phase of an ongoing project to develop reliable bedside monitoring of patients undergoing ototoxic medical treatment.     

Dietary polyunsaturated fat decreases coronary artery atherosclerosis in a pediatric-aged population of African green monkeys

The hypothesis tested was that juvenile African green monkeys consuming diets enriched with n-6 polyunsaturated fat from birth until young adulthood would have significantly less coronary artery atherosclerosis than comparable animals consuming diets enriched with saturated fat. African green monkeys (Cercopithecus aethiops, n = 108) of both sexes were fed atherogenic diets (0.8 mg cholesterol/kcal) throughout their lives so that death at 16, 32, or 60 months of age permitted quantification of atherosclerosis. In the coronary arteries, the average intimal area increased significantly with age (P = .02), showing increases of 28-fold and sevenfold between 32 and 60 months in the saturated fat- and polyunsaturated fat-fed groups, respectively. Young adult male animals at 60 months of age were found to have significantly (P = .03) more coronary artery atherosclerosis than female animals. Animals fed polyunsaturated fat had significantly (P < or = .01) less coronary artery atherosclerosis. By 60 months of age in the animals consuming polyunsaturated fat, the average coronary artery intimal area was one fourth and the average size of the largest coronary intimal lesion was one fifth that in monkeys fed saturated fat. Low-density lipoprotein (LDL) cholesterol and LDL particle size were each found to be positively correlated with coronary artery atherosclerosis end points in both diet groups. In addition to the coronary arteries, atherosclerosis in the abdominal and thoracic aorta and carotid arteries was also evaluated; the coronary arteries were the only arterial system with significantly less atherosclerosis in the polyunsaturated fat group as measured by intimal area. However, evaluation of histological sections of abdominal aorta showed relatively more sterol clefts in the saturated fat-fed group, and more free cholesterol was measured, suggesting that lesions were more complicated in this group. These results show that dietary intervention early in life with n-6 polyunsaturated fat can be effective in decreasing the development of atherosclerosis, particularly in the coronary arteries of primates. This outcome supports the concept that dietary intervention beginning early in childhood can have beneficial effects on the coronary heart disease of later life.     

Host factors that influence the duration of menstrual bleeding

We assessed the association between weight, exercise, and stress and the duration of menstrual bleeding in a 1-year prospective menstrual diary study of 166 college first-year women, age 17-19 years. Low weight-for-height increased expected bleed duration by 0.39 day. Dieting to lose weight reduced bleed length by 0.43 day. Women who did no moderate or hard exercise bled about a quarter of a day longer than women at the median level of physical activity.