Apolipoprotein E metabolism in normolipoproteinemic human subjects

Human apolipoprotein E (apoE) is a constituent of plasma very low density and high density lipoproteins and is important in modulating the catabolism of remnants of triglyceride-rich lipoproteins. There are three common isoforms of apoE, designated apoE-2, E-3, and E-4, which are coded by three separate alleles (epsilon 2, epsilon 3, and epsilon 4) at a single genetic locus and inherited in the population in a co-dominant fashion. ApoE-3 is the predominant apoE isoform in the normolipidemic population, and epsilon 3 has been proposed to be the normal allele. ApoE-3 metabolism was studied in nine normolipidemic subjects homozygous for the epsilon 3 allele. In these subjects, the plasma apoE-3 concentration was 4.8 +/- 1.2 mg/dl (mean +/- SD), the plasma apoE-3 residence time was 0.73 +/- 0.18 days, and the plasma apoE-3 production rate was 3.4 +/- 1.5 mg/kg-day. The apoE in males, when compared to females, tended to have a shorter residence time (0.63 +/- 0.15 days versus 0.83 +/- 0.16), a higher production rate (4.20 +/- 1.73 mg/kg-days versus 2.60 +/- 0.78), but a similar plasma concentration (5.1 +/- 1.5 mg/dl versus 4.5 +/- 0.8). ApoE-3 had a more rapid catabolism from plasma than other apolipoproteins previously studied (apolipoproteins A-I, A-II, A-IV, B-100, C-II, and C-III) except for apolipoprotein B-48. The catabolism of apoE-3 in the individual lipoprotein subfractions was also examined and apoE was shown to be catabolized most rapidly from the VLDL and slowest from the HDL. The results of the kinetic analysis of apoE metabolism are consistent with apoE being important in the catabolism of triglyceride-rich lipoproteins and with HDL serving as a reservoir for apoE to reassociate with newly secreted triglyceride-rich lipoproteins.     

Normal and abnormal fetal growth

The fetal origins of adult disease hypothesis suggests that poor intrauterine growth is associated with an increased risk of cardiovascular disease. The hypothesis goes on to implicate different growth 'phenotypes', particularly disproportionate growth, in the determination of the type of cardiovascular disease that develops. Analysis of the antenatal growth of a low-risk pregnancy population does not identify such growth phenotypes within the general population. Rather, intrauterine growth is characterized by poor predictability of subsequent size, suggesting that centile crossing is a common feature of intrauterine growth. Furthermore, there is a sexually dimorphic pattern to this growth that needs to be considered in further work to test the fetal origins hypothesis.     

Changes in zinc metabolism following exercise in human subjects

Changes in zinc (Zn) availability in muscle tissue that influence muscle performance in vitro have been observed. The effect of exercise of plasma Zn levels and urinary excretion of Zn was observed in sever untrained volunteers following brief intensive exercise and in seven trained volunteers after more prolonged road-running exercise. With brief exercise, plasma Zn decreased predominantly in the more loosely bound albumin fraction. Prolonged exercise resulted in a greater plasma Zn decrease of 30%. Urinary Zn excretion increased transiently with minimal effect on daily losses. However, weight loss by sweating was significant, and sweat Zn losses were greater than those in the urine. Exercise resulted in changes in Zn metabolism that may influence performance.     

Normal and abnormal biosynthesis of gangliosides

The carbohydrate portion of gangliosides, the sialylglycolipids associated with neural tissues, are synthesized in an ordered step-wise process by a group of glycosyltransferases that appear to exist as a multi-enzyme complex in the Golgi apparatus. The composition of gangliosides in various tissues and cultured cells reflects the presence or absence of specific glycosyltransferase activities. Ganglioside biosynthesis appears to be regulated and may be induced during development and differentiation. Gangliosides in turn can function as specific cell surface receptors and may be involved in morphological changes.Absence of specific glycosyltransferase activities is associated with an abnormal pathology. Altered ganglioside biosynthesis is common in cultured cells transformed by a variety of oncogenic agents as well as in neoplasias. In addition, a patient with a deficient aminosugar transferase recently has been identified and may represent a new class of metabolic diseases, the anabolic sphingolipidoses.     

Studies on the structure and metabolism of glycogen in some abnormal human infants

1. The liver and muscle tissues of 14 human anencephalic babies were examined for glycogen content and structure, and for the activities of several glycogen-metabolizing enzymes. 2. In both tissues glycogen content increased with gestation age; the muscle glycogens had a slightly but significantly lower degree of branching than the corresponding liver glycogens. 3. All the expected glycogen-metabolizing enzymes were present; acid maltase activities were higher and phosphoglucomutase activities were lower than the results reported for human adult tissues. Glucose 6-phosphatase activity increased significantly with gestation age.     

Normal versus abnormal cell proliferation

The most recent findings on the molecular and cellular characterization of normal and abnormal cell proliferation are summarized. They include molecular spectroscopy, nucleic acid conformation, protein modifications, premature chromosome condensation, nuceoli changes, nuclear and cell morphometry, image analysis, flow microfluorimetry, and time-lapse cinematography. Biophysical and biochemical evidence in favor or against two cycles of chromatin condensation, followed by two abrupt random decondensations, per cell cycle are presented. Other biphasic changes at the molecular and cellular levels that favor the existence of two random transitions, or restriction points, per cell cycle are discussed. A comprehensive unitary model of the cell cycle is then outlined; this model is able to explain most findings on continuously dividing cells and on quiescent cells induced to proliferate. Within this analytical framework the physical-chemical and biological properties are given, in either normal or tumor cells, for the various types of “noncycling” cells that are here viewed as necessary steps in mammalian cell growth rather than separate states. The implications of the coupling of higher-order chromatin structure with cell geometry and growth, high in fibroblast-like cells but low in transformed cells, are also discussed. Molecular mechanisms likely responsible for the chromatin conformational changes occurring at the G₀→G₁, G₁→S, G₂→M transitions are finally discussed in terms of polyelectrolyte theory.     

Normal and abnormal epithelial differentiation in the female reproductive tract

In mammals, the female reproductive tract (FRT) develops from a pair of paramesonephric or Müllerian ducts (MDs), which arise from coelomic epithelial cells of mesodermal origin. During development, the MDs undergo a dynamic morphogenetic transformation from simple tubes consisting of homogeneous epithelium and surrounding mesenchyme into several distinct organs namely the oviduct, uterus, cervix and vagina. Following the formation of anatomically distinctive organs, the uniform MD epithelium (MDE) differentiates into diverse epithelial cell types with unique morphology and functions in each organ. Classic tissue recombination studies, in which the epithelium and mesenchyme isolated from the newborn mouse FRT were recombined, have established that the organ specific epithelial cell fate of MDE is dictated by the underlying mesenchyme. The tissue recombination studies have also demonstrated that there is a narrow developmental window for the epithelial cell fate determination in MD-derived organs. Accordingly, the developmental plasticity of epithelial cells is mostly lost in mature FRT. If the signaling that controls epithelial differentiation is disrupted at the critical developmental stage, the cell fate of MD-derived epithelial tissues will be permanently altered and can result in epithelial lesions in adult life. A disruption of signaling that maintains epithelial cell fate can also cause epithelial lesions in the FRT. In this review, the pathogenesis of cervical/vaginal adenoses and uterine squamous metaplasia is discussed as examples of such incidences.     

Simulation of cell behavior: Normal and abnormal growth

A mathematical model simulating a cell growing in a culture medium is obtained. Using this model, various behavioral patterns of the cell are obtained under different types of disturbances, in particular when (i) a Mg2+ deficiency experiment and, (ii) a split-dose ionizing radiation experiment are carried out, (iii) when disturbances on the rate constants of the biochemical reactions taking place in the nucleus of the cell are applied, and (iv) when the cell's interior components are perturbed. The cell model results obtained agree well with experimental results for the Mg2+ and split dose experiments, and explain the mechanism of the split dose radiation experiment without the need to introduce additional axioms (e.g. healing processes) into the dynamics of the cell. Conditions are obtained which cause the cell to behave in a rapidly growing 'tumor-like' mode; it is shown that once the cell moves into this 'tumor-like; mode, its behavior is irreversible, i.e. if a disturbance of opposite type is then applied to the 'tumor cell, the cell will not revert back to its original normal behavior.     

Normal copper metabolism in quaking mice

This research measured lipid peroxidation products in rats of varying age by a new method. Wistar male rats, 4, 12, 22 and 32 months old, were examined for lipid peroxidation in vivo by measurement of ethane, ethylene, butane and pentane in breath gases of intact animals. In the older rats, the amounts of the four hydrocarbons exhaled were greater than those in younger rats. All hydrocarbons tested were related to age by an exponential relationship, and quantitatively, ethane and ethylene were related to age with a linear regression fit correlation coefficient, 0.466–0.622 (p<0.01-0.001). When hydrocarbon gas production of 32 month-old rats was compared with that of 4 month-old rats, the greatest ratio was that for pentane (1.99). The following order was ethylene >ethane>butane. There were significant differences in the production of all hydrocarbons between 32 month-old rats and 4 month-old rats.Thiobarbituric acid reactants in serum exhibited an increasing tendency with age, but the values of 32 month-old rats were lower than those of 22 month-old rats. However, the differences between the age groups were not significant.These results showed that the measurement of hydrocarbons in the rats'breath was a sensitive index of in vivo peroxidation during aging.