Auxin: its role in genetic tumor induction

Seedlings of the tumor-prone amphiploid Nicotiana suaveolens X N. langsdorffii were grown on nutrient medium supplemented with indoleacetic acid (IAA) and scored at regular intervals for the incidence of tumor formation. IAA at 2 x 10(-5)m caused a significant reduction in the rate of tumor formation. Plants were also grown on nutrient medium under two different intensities of illumination, and the endogenous level of IAA was determined in 23-day-old seedlings. Those grown under 2000 ft-c of illumination had a higher incidence of tumors and a significantly lower level of endogenous IAA than those grown under 500 ft-c of illumination. A correlation in time between decline in the endogenous level of IAA and onset of tumor formation was demonstrated in greenhouse-grown plants.     

Environmental enrichment committee: its role in program development

The authors discuss the role of the Environmental Enrichment Committee in developing, implementing, assessing, and modifying a university animal enrichment program.     

Compartmental efflux analysis: an evaluation of the technique and its limitations

Efflux analysis is an established tool for characterizing the exchange properties of multicomponent systems. In this report, we have simulated several three- and four-compartment systems with error-free and imperfect data, the errors being designed to mimic actual, nonbiological variability in isotope efflux studies. The data sets were analyzed using computerized nonlinear regression techniques to identify the important aspects of actual experimental design (uptake times, efflux collection schedules, and total efflux times), and to consider the possibility that a properly designed and executed experiment might fail to resolve compartmentation correctly. The results showed that for any of the systems simulated, including those with error-free four-component data, a reasonable three-component fit was obtainable. Resolution of the additional compartment was not always possible. In correctly resolved systems, failure to estimate the correct decay constants was common, especially when the half-times were separated by less than an order of magnitude. We conclude that efflux analysis, by itself, lacks the power to provide reliable information about multicompartment systems.     

Genetic epidemiology, genetic maps and positional cloning

Genetic epidemiology developed in the middle of the last century, focused on inherited causes of disease but with methods and results applicable to other traits and even forensics. Early success with linkage led to the localization of genes contributing to disease, and ultimately to the Human Genome Project. The discovery of millions of DNA markers has encouraged more efficient positional cloning by linkage disequilibrium (LD), using LD maps and haplotypes in ways that are rapidly evolving. This has led to large international programmes, some promising and others alarming, with laws about DNA patenting and ethical guidelines for responsible research still struggling to be born.     

Path analysis in genetic epidemiology: a critique

Path analysis, a form of general linear structural equation models, is used in studies of human genetics data to discern genetic, environmental, and cultural factors contributing to familial resemblance. It postulates a set of linear and additive parametric relationships between phenotypes and genetic and cultural variables and then essentially uses the assumption of multivariate normality to estimate and perform tests of hypothesis on parameters. Such an approach has been advocated for the analysis of genetic epidemiological data by D. C. Rao, N. Morton, C. R. Cloninger, L. J. Eaves, and W. E. Nance, among others. This paper reviews and evaluates the formulations, assumptions, methodological procedures, interpretations, and applications of path analysis. To give perspective, we begin with a discussion of path analysis as it occurs in the form of general linear causal models in several disciplines of the social sciences. Several specific path analysis models applied to lipoprotein concentrations, IQ, and twin data are then reviewed to keep the presentation self-contained. The bulk of the critical discussion that follows is directed toward the following four facets of path analysis: (1) coherence of model specification and applicability to data; (2) plausibility of modeling assumptions; (3) interpretability and utility of the model; and (4) validity of statistical and computational procedures. In the concluding section, a brief discussion of the problem of appropriate model selection is presented, followed by a number of suggestions of essentially model-free alternative methods of use in the treatment of complex structured data such as occurs in genetic epidemiology.     

Pathogenic RNA repeats: an expanding role in genetic disease

Fragile X mental retardation and Friedreich's ataxia were among the first pathogenic trinucleotide repeat disorders to be described in which noncoding repeat expansions interfere with gene expression and cause a loss of protein production. Invoking a similar loss-of-function hypothesis for the CTG expansion causing myotonic dystrophy type 1 (DM1) located in the 3' noncoding portion of a kinase gene was more difficult because DM is a dominantly inherited multisystemic disorder in which the second copy of the gene is unaffected. However, the discovery that a transcribed but untranslated CCTG expansion causes myotonic dystrophy type 2 (DM2), along with other discoveries on DM1 and DM2 pathogenesis, indicate that the CTG and CCTG expansions are pathogenic at the RNA level. This review will detail recent developments on the molecular mechanisms of RNA pathogenesis in DM, and the growing number of expansion disorders that might involve similar pathogenic RNA mechanisms.     

Biostatistics and epidemiology: measuring the risk attributable to an environmental or genetic factor

Disease frequency is measured through estimating incidence rates or disease risk. Several measures are used for assessing exposure-disease association, with adjusted estimates based on standardization, stratification, or more flexible regression techniques. Several measures are available to assess an exposure impact in terms of disease occurrence at the population level, including the commonly used attributable risk (AR). Adjusted AR estimation relies on stratification or regression techniques. Sequential and partial ARs have been proposed to handle the situation of multiple exposures and circumvent the associated non-additivity problem. Despite remaining issues in properly interpreting AR, AR remains a useful guide to assess prevention strategies.     

Recurrence and prognostic factors in patients with aggressive fibromatosis. The role of radical surgery and its limitations

ABSTRACT: BACKGROUND: Surgery is still the standard treatment for aggressive fibromatosis (AF); however, local control remains a significant problem and the impact of R0 surgery on cumulative recurrence (CR) is objective of contradictory reports. METHODS: This is a single-institution study of 62 consecutive patients affected by extra-abdominal and intra-abdominal AF who received macroscopically radical surgery within a time period of 15 years. RESULTS: Definitive pathology examination confirmed an R0 situation in 49 patients and an R1 in 13 patients. Five-year CR for patients who underwent R0 vs R1 surgery was 7.1% vs 46.4% (P = 0.04) and for limbs vs other localizations 33.3% vs 9.9% (P = 0.02) respectively. In 17 patients who had intraoperative frozen section (IFS) margin evaluation R0 surgery was more common (17 of 17 vs 32 of 45, P = 0.01) and CR lower (five-year CR 0% vs 19.1%, respectively, P = 0.04). However, in multivariate analysis only limb localization showed a negative impact on CR (HR: 1.708, 95% CI 1.03 to 2.84, P = 0.04). CONCLUSIONS: IFS evaluation could help the surgeon to achieve R0 surgery in AF. Non-surgical treatment, including watchful follow-up, could be indicated for patients with limb AF localization, because of their high risk of recurrence even after R0 surgery.     

The genetic epidemiology of leprosy in a Brazilian population.

Data on leprosy patients have been obtained from the Dispensary of Leprosy of Campinas, São Paulo, where records on practically all cases of leprosy in the Campinas area during the period 1960-70 are filed. The whole sample comprises 10,886 individuals, distributed among 1,568 families. Complex segregation analysis was utilized to determine the nature of the genetic factors that may operate on leprosy and its subtypes. The results suggest the presence of a recessive major gene controlling susceptibility to leprosy per se, with frequency of approximately .05, although there are deviations from the expected Mendelian segregation proportions. Possible etiologic heterogeneity was examined by considering two subtypes separately: for lepromatous leprosy and tuberculoid leprosy there are suggestions for a segregating major effect; however, Mendelian transmission could not be demonstrated in either case. Therefore, there is no evidence to suggest unique genetic determinants for leprosy subtypes.     

Anaerobic L- -glycerophosphate dehydrogenase of Escherichia coli: its genetic locus and its physiological role

In mutant cells of Escherichia coli missing the particulate l-alpha-glycerophosphate (l-alpha-GP) dehydrogenase necessary for aerobic growth on glycerol or l-alphaGP, a soluble, flavine-dependent l-alpha-GP dehydrogenase supports normal anaerobic growth rates on either of the two substrates with fumarate or nitrate as exogenous hydrogen acceptor. In an experiment in which glycerol served as the carbon source and nitrate as the acceptor, the growth of such a mutant was arrested upon the admission of air, whereas the growth of wild-type cells continued smoothly. Mutant cells lacking the soluble l-alpha-GP dehydrogenase, but possessing the particulate enzyme, can grow at normal rates aerobically on glycerol and l-alpha-GP or anaerobically on these compounds with nitrate, but not fumarate, as the hydrogen acceptor. Double mutants lacking both of the dehydrogenases fail to show significant growth on either glycerol or l-alpha-GP under any condition. Mutations affecting the anaerobic dehydrogenase (glpA locus) are situated at about minute 43 of the Taylor map, just clockwise beyond glpT, and show cotransduction with purF (1.5%), glpT (91%), and nalA (50%). The anaerobic dehydrogenase is a member of the glp regulon as judged by its inducibility by l-alpha-GP and by its constitutive formation in strains of glpR(c) genotype. The level of the anaerobic dehydrogenase is about the same in cells grown either aerobically or anaerobically with nitrate serving as a terminal hydrogen acceptor. With fumarate as terminal acceptor, the level is elevated several fold.     

Microneurography: how the technique developed and its role in the investigation of the sympathetic nervous system.

A historical review is given of the development of microneurography and its application for studies of sympathetic nerve activity in humans.     

The mTOR pathway and its role in human genetic diseases

The signalling components upstream and downstream of the protein kinase mammalian target of rapamycin (mTOR) are frequently altered in a wide variety of human diseases. Upstream of mTOR key signalling molecules are the small GTPase Ras, the lipid kinase PI3K, the Akt kinase, and the GTPase Rheb, which are known to be deregulated in many human cancers. Mutations in the mTOR pathway component genes TSC1, TSC2, LKB1, PTEN, VHL, NF1 and PKD1 trigger the development of the syndromes tuberous sclerosis, Peutz-Jeghers syndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos disease, Proteus syndrome, von Hippel-Lindau disease, Neurofibromatosis type 1, and Polycystic kidney disease, respectively. In addition, the tuberous sclerosis proteins have been implicated in the development of several sporadic tumors and in the control of the cyclin-dependent kinase inhibitor p27, known to be of relevance for several cancers. Recently, it has been recognized that mTOR is regulated by TNF-alpha and Wnt, both of which have been shown to play critical roles in the development of many human neoplasias. In addition to all these human diseases, the role of mTOR in Alzheimer's disease, cardiac hypertrophy, obesity and type 2 diabetes is discussed.