Role of genetic variability in neonatal jaundice. A prospective study on full-term,blood group-compatible infants

A series of genetic, developmental and environmental variables have been analyzed in a prospective sample of full-term newborn babies, compatible with their mothers in the major blood group systems, in order to attempt an evaluation of the effect of these variables on serum bilirubin level during the first few days of life. Three genetic factors (PGM₁, ACP₁ and ADA) and three non-genetic variables (rise of bilirubin level during the first day of life, a mother with a history of previous abortion, and use of alcoholic beverages by the mother) have a significant predictive value for the separation of newborns with clinically relevant jaundice from other infants.     

Nature/nurture and the nature of nurture in the etiology of hypertension.

Four reviews on the the role of developmental factors in hypertension are introduced and set in historical context. Recent research in the laboratory rat has shown that the preweaning environment makes an important contribution to the level of blood-pressure reached in adult life in genetic models of hypertension. Both of the most commonly used models of hypertension, the SHR and SS/Jr rat strains, exhibit lower BP in adult life, if they are fostered shortly after birth to mothers from their normotensive control strains. It has been suggested that it is the idiosyncratic maternal behavior of the hypertensive mothers which contributes to the elevated BP of their offspring, and it has been amply demonstrated that there is an association between a constellation of behaviors emitted by rat mothers and the adult BP of their offspring in a wide variety of genetic groups (inbred hypertensive animals, F1's and F2's). In addition to the above, maternal environment has been demonstrated to have a significant impact on the pathophysiological response of hypertensive animals to a high salt diet. Being raised by an SHR mother, versus an SS/Jr mother, increases the magnitude of BP increases to a high salt diet, susceptibility to hemorrhagic stroke, body weight loss and the risk of mortality. A variety of physiological systems are undergoing rapid change during the preweaning period and may mediate the effects of differences in the maternal environment. These include the renin-angiotensin system and the peripheral sympathetic nervous system. Nutritional factors may be involved in all of the phenomena referred to above. Thus, any physiological mechanisms that are proposed to link maternal behavior to its effects on the physiology of adult animals should recognize the involvement of nutritional factors. Research on the role of developmental factors such as maternal behavior in genetic models of hypertension is at the interface of two growing disciplines: behavior genetics and developmental psychobiology. The methodological and conceptual contributions of these fields to advancing our understanding of these phenomena is emphasized.     

Genetic models in brain and behavior research,part IV

Four reviews on the the role of developmental factors in hypertension are introduced and set in historical context. Recent research in the laboratory rat has shown that the preweaning environment makes an important contribution to the level of blod-pressure reached in adult life in genetic models of hypertension. Both of the most commonly used models of hypertension, the SHR and SS/Jr rat strains, exhibit lower BP in adult life, if they are fostered shortly after birth to mothers from their normotensive control strains. It has been suggested that it is the idiosyncratic maternal behavior of the hypertensive mothers which contributes to the elevated BP of their offspring, and it has been amply demonstrated that there is an association between a constellation of behaviors emitted by rat mothers and the adult BP of their offspring in a wide variety of genetic groups (inbred hypertensive animals, F1's and F2's). In addition to the above, maternal environment has been demonstrated to have a significant impact on the pathophysiological response of hypertensive animals to a high salt diet. Being raised by an SHR mother, versus an SS/Jr mother, increases the magnitude of BP increases to a high salt diet, susceptibility to hemorrhagic stroke, body weight loss and the risk of mortality. A variety of physiological systems are undergoing rapid change during the preweaning period and may mediate the effects of differences in the maternal environment. These include the renin-angiotensin system and the peripheral sympathetic nervous system. Nutritional factors may be involved in all of the phenomena referred to above. Thus, any physiological mechanisms that are proposed to link maternal behavior to its effects on the physiology of adult animals should recognize the involvement of nutritional factors. Research on the role of developmental factors such as maternal behavior in genetic models of hypertension is at the interface of two growing disciplines: behavior genetics and developmental psychobiology. The methodological and conceptual contributions of these fields to advancing our understanding of these phenomena is emphasized.     

Sexual maturation in female rats: Hereditary,developmental and environmental aspects

Two physiological components of sexual maturation, vaginal opening and first estrus, apparently evolve similarly in Wistar and Sprague-Dawley rats. However, a bimodal distribution in the frequency of the days of vaginal opening is observed within a given strain, which is less related to heredity than to the timing and type of experiment. In addition, when the modulators of sexual maturation are reviewed, it can be observed that sensitivity to external stimuli can vary even within a strain. For a defined set of breeding conditions, one group of rats can be more susceptible to changes in the lighting regimen and not be affected by controlled stressors, while another group responds more to stress and less to light. The reason for susceptibility to one rather than another environmental factor under similar breeding conditions is not understood. In that context, it is difficult to evaluate the role of heredity when we cannot understand the full impact of the environment, not to mention maternal influence in fetal and early life. Using two lines of psychogenetically selected rats, it was possible to show that they had differences in sexual maturation, which strongly suggested a genetic predisposition. Nevertheless, the question arises as to whether the genetic locus directly affects organs implicated in sexual maturation or whether it acts on some unknown factor which only secondarily modifies sexual maturation. In summary, there is more need to understand the role of the environment, including that of the mother early in fetal and neonatal life. It is suggested that the mechanisms underlying organ growth are set for a given species, while developmental and environmental factors fix the timing of vaginal opening and first ovulation. In the rat, there appear to be two times which are preferred for vaginal opening, given the laboratory conditions that have been used in the last 20 or so years: an early period, at 31–35 days, and a late period, at 36–40 days. An explanation for this dichotomy would be that a combination of parameters (not necessarily always the same) is needed for vaginal opening. These parameters oscillate during sexual maturation with different frequencies, which can achieve resonance to lead to vaginal opening and ovulation only during given periods.     

Sexual maturation in female rats: hereditary, developmental and environmental aspects

Two physiological components of sexual maturation, vaginal opening and first estrus, apparently evolve similarly in Wistar and Sprague-Dawley rats. However, a bimodal distribution in the frequency of the days of vaginal opening is observed within a given strain, which is less related to heredity than to the timing and type of experiment. In addition, when the modulators of sexual maturation are reviewed, it can be observed that sensitivity to external stimuli can vary even within a strain. For a defined set of breeding conditions, one group of rats can be more susceptible to changes in the lighting regimen and not be affected by controlled stressors, while another group responds more to stress and less to light. The reason for susceptibility to one rather than another environmental factor under similar breeding conditions is not understood. In that context, it is difficult to evaluate the role of heredity when we cannot understand the full impact of the environment, not to mention maternal influence in fetal and early life. Using two lines of psychogenetically selected rats, it was possible to show that they had differences in sexual maturation, which strongly suggested a genetic predisposition. Nevertheless, the question arises as to whether the genetic locus directly affects organs implicated in sexual maturation or whether it acts on some unknown factor which only secondarily modifies sexual maturation. In summary, there is more need to understand the role of the environment, including that of the mother early in fetal and neonatal life. It is suggested that the mechanisms underlying organ growth are set for a given species, while developmental and environmental factors fix the timing of vaginal opening and first ovulation. In the rat, there appear to be two times which are preferred for vaginal opening, given the laboratory conditions that have been used in the last 20 or so years: an early period, at 31-35 days, and a late period, at 36-40 days. An explanation for this dichotomy would be that a combination of parameters (not necessarily always the same) is needed for vaginal opening. These parameters oscillate during sexual maturation with different frequencies, which can achieve resonance to lead to vaginal opening and ovulation only during given periods.     

Zinc,copper and selenium in reproduction

Of the nine biological trace elements, zinc, copper and selenium are important in reproduction in males and females. Zinc content is high in the adult testis, and the prostate has a higher concentration of zinc than any other organ of the body. Zinc deficiency first impairs angiotensin converting enzyme (ACE) activity, and this in turn leads to depletion of testosterone and inhibition of spermatogenesis. Defects in spermatozoa are frequently observed in the zinc-deficient rat. Zinc is thought to help to extend the functional life span of the ejaculated spermatozoa. Zinc deficiency in the female can lead to such problems as impaired synthesis/secretion-of (FSH) and (LH), abnormal ovarian development, disruption of the estrous cycle, frequent abortion, a prolonged gestation period, teratogenicity, still-births, difficulty in parturition, pre-eclampsia, toxemia and low birth weights of infants. The level of testosterone in the male has been suggested to play a role in the severity of copper deficiency. Copper-deficient female rats are protected against mortality due to copper deficiency, and the protection has been suggested to be provided by estrogens, since estrogens alter the subcellular distribution of copper in the liver and increase plasma copper levels by inducing ceruloplasmin synthesis. The selenium content of male gonads increases during pubertal maturation. Selenium is localized in the mitochondrial capsule protein (MCP) of the midpiece. Maximal incorporation in MCP occurs at steps 7 and 12 of spermatogenesis and uptake dereases by step 15. Selenium deficiency in females results in infertility, abortions and retention of the placenta. The newborns from a selenium-deficient mother suffer from muscular weakness, but the concentration of selenium during pregnancy does not have any effect on the weight of the baby or length of pregnancy. The selenium requirements of a pregnant and lactating mother are increased as a result of selenium transport to the fetus via the placenta and to the infant via breast milk.     

Quantitative genetics of zooplankton life histories

Quantitative genetic techniques are powerful tools for use in understanding the microevolutionary process. Because of their size, lifespan, and ease of culture, many zooplankton species are ideal for quantitative genetic approaches. As model systems, studies of zooplankton life histories are becoming increasingly used for examination of the central paradigms of evolutionary theory. Two of the fundamental empirical questions that zooplankton quantitative genetics studies can answer are: 1) How much genetic variance exists in natural populations for life history traits? 2) What is the empirical evidence for trade-offs that permeate life history theory based on optimality approaches? A review of existing data onDaphnia indicates substantial genetic variance for body size, clutch size, and age at first reproduction. Average broad-sense heritabilities for these three characters across 19 populations of 6 species are 0.31, 0.31, and 0.34, respectively. Although there is some discrepancy between the two pertinent studies that were designed to decompose the total genetic variance into its additive and non-additive components, a crude average seems to suggest that approximately 60% of the total genetic variance has an additive basis. The existing data are somewhat inconsistent with respect to presence/absence of trade-offs (negative genetic correlations) among life history traits. A composite of the existing data seems to argue against the existence of strong trade-offs between offspring size and offspring number, between present and future reproduction, and between developmental rate and fecundity. However, there is some evidence for a shift toward more negative (less positive) covariances in more stressful environments (e.g., low food). Zooplankton will prove to be very useful in future study in several important areas of research, including the genetics and physiology of aging, the importance of genotype-environment interaction for life history traits, and the evolution of phenotypic plasticity.     

ABO system incompatibility: evaluation of risk of hyperbilirubinaemia at birth by multivariate discriminant analysis

Summary A discriminant analysis was performed on a set of maternal and neonatal variables to predict at birth the serum bilirubin levels during the neonatal period in infants incompatible with their mothers in the ABO system. The results suggest that the rational and simultaneous utilization of clinical and laboratory parameters allows, a few hours after delivery, a useful classification of these infants in low or high risk for hyperbilirubinemia.This work was supported by grants of NATO, Italian CNR and M.P.I.     

Endonuclease V: an unusual enzyme for repair of DNA deamination

Endonuclease V (endo V) was first discovered as the fifth endonuclease in Escherichia coli in 1977 and later rediscovered as a deoxyinosine 3′ endonuclease. Decades of biochemical and genetic investigations have accumulated rich information on its role as a DNA repair enzyme for the removal of deaminated bases. Structural and biochemical analyses have offered invaluable insights on its recognition capacity, catalytic mechanism, and multitude of enzymatic activities. The roles of endo V in genome maintenance have been validated in both prokaryotic and eukaryotic organisms. The ubiquitous nature of endo V in the three domains of life: Bacteria, Archaea, and Eukaryotes, indicates its existence in the early evolutionary stage of cellular life. The application of endo V in mutation detection and DNA manipulation underscores its value beyond cellular DNA repair. This review is intended to provide a comprehensive account of the historic aspects, biochemical, structural biological, genetic and biotechnological studies of this unusual DNA repair enzyme.     

Fine structure of differentiated chromosome segments during the meiosis of pollen mother cells of Allium cepa

Summary Differentiated chromosome segments were observed during studies of pollen mother cells of A. cepa during the first meiotic division. Their structure is like those of the nucleolar organizing region (NOR) described in A. cepa microspores. It is suggested that these differentiated chromosome segments correspond to the secondary constrictions seen under the optical microscope.     

Quantitative Bestimmung von RNS-Fraktionen im Gehirn frisch geschlüpfter Bienen (Apis mellifica)

Summary In the brain of the honeybee (Apis mellifica), it was found that the rRNA content decreases rapidly during the first 2 days of adult life. An increase is observed from days 3 to 5, followed by another decrease to a level inferior to that of day 2 to 3. Except for a rise on the 5th day, 4s RNA remains constant. An unidentified RNA fraction of low molecular weight (D) sharply decreases on day 5. The possibility is discussed that these results reflect changes in RNA metabolism that can be related to the sequences of activity observed in the bees during the first 9 days after hatching.     

Forecasting euro area variables with German pre‐EMU data

It is investigated whether euro area variables can be forecast better based on synthetic time series for the pre‐euro period or by using just data from Germany for the pre‐euro period. Our forecast comparison is based on quarterly data for the period 1970Q1–2003Q4 for 10 macroeconomic variables. The years 2000–2003 are used as forecasting period. A range of different univariate forecasting methods is applied. Some of them are based on linear autoregressive models and we also use some nonlinear or time‐varying coefficient models. It turns out that most variables which have a similar level for Germany and the euro area such as prices can be better predicted based on German data, while aggregated European data are preferable for forecasting variables which need considerable adjustments in their levels when joining German and European Monetary Union (EMU) data. These results suggest that for variables which have a similar level for Germany and the euro area it may be reasonable to consider the German pre‐EMU data for studying economic problems in the euro area. Copyright © 2008 John Wiley & Sons, Ltd.     

Bioaccumulation processes in ecosystems.

The fate of environmental pollutants--the various isotopes of elements, and inorganic or organic compounds--is a fundamental aspect of ecology and ecotoxicology, and bioaccumulation is a phenomenon often discussed in this context. Human activities have drastically altered natural concentrations of many substances in the environment and added numerous new chemicals. An understanding of the processes of bioaccumulation is important for several reasons. 1) Bioaccumulation in organisms may enhance the persistence of industrial chemicals in the ecosystem as a whole, since they can be fixed in the tissues of organisms. 2) Stored chemicals are not exposed to direct physical, chemical, or biochemical degradation. 3) Stored chemicals can directly affect an individual's health. 4) Predators of those organisms that have bioaccumulated harmful substances may be endangered by food chain effects. While former theories on the processes of bioaccumulation focused on single aspects that affect the extent of accumulation (such as the trophic level within the food chain or the lipophilicity of the chemical), modern theories are based on compartmental kinetics and the integration of various environmental interactions. Concepts include results from quantitative structure-activity relationships (QSAR), pharmacokinetics, ecophysiology and general biology, molecular genetic aspects and selection, and finally the structure of communities and man-made alterations in them.     

Molecular processes involved in B cell acute lymphoblastic leukaemia

B cell leukaemia is one of the most frequent malignancies in the paediatric population, but also affects a significant proportion of adults in developed countries. The majority of infant and paediatric cases initiate the process of leukaemogenesis during foetal development (in utero) through the formation of a chromosomal translocation or the acquisition/deletion of genetic material (hyperdiploidy or hypodiploidy, respectively). This first genetic insult is the major determinant for the prognosis and therapeutic outcome of patients. B cell leukaemia in adults displays similar molecular features as its paediatric counterpart. However, since this disease is highly represented in the infant and paediatric population, this review will focus on this demographic group and summarise the biological, clinical and epidemiological knowledge on B cell acute lymphoblastic leukaemia of four well characterised subtypes: t(4;11) MLL-AF4, t(12;21) ETV6-RUNX1, t(1;19) E2A-PBX1 and t(9;22) BCR-ABL1.     

Regulation of the cell cycle following DNA damage in normal and Ataxia telangiectasia cells

A proportion of the population is exposed to acute doses of ionizing radiation through medical treatment or occupational accidents, with little knowledge of the immedate effects. At the cellular level, ionizing radiation leads to the activation of a genetic program which enables the cell to increase its chances of survival and to minimize detrimental manifestations of radiation damage. Cytotoxic stress due to ionizing radiation causes genetic instability, alterations in the cell cycle, apoptosis, or necrosis. Alterations in the G1, S and G2 phases of the cell cycle coincide with improved survival and genome stability. The main cellular factors which are activated by DNA damage and interfere with the cell cycle controls are: p53, delaying the transition through the G1-S boundary; p21^WAF1/CIPI, preventing the entrance into S-phase; proliferating cell nuclear antigen (PCNA) and replication protein A (RPA), blocking DNA replication; and the p53 variant protein p53as together with the retinoblastoma protein (Rb), with less defined functions during the G2 phase of the cell cycle. By comparing a variety of radioresistant cell lines derived from radiosensitive ataxia talangiectasia cells with the parental cells, some essential mechanisms that allow cells to gain radioresistance have been identified. The results so far emphasise the importance of an adequate delay in the transition from G2 to M and the inhibition of DNA replication in the regulation of the cell cycle after exposure to ionizing radiation.     

Solubilization of unconjugated bilirubin by bile salts.

Freshly precipitated unconjugated bilirubin (UCB) is solubilized rapidly and to a large extent by the sodium salts of di- and trihydroxy bile acids. The solubilization effect depending on bile salt concentration, pH and ionic strength is based on micellar mechanisms.     

The relations between G-6-PD deficiency,thalassemia and malaria. Further analysis of data from Sardinia and the Po Valley

Summary Discriminant analysis carried out on a set of environmental and sociocultural variables in the Sardinian population suggests that G-6-PD deficiency and thalassemia move along 2 dimensions partially independent of each other. Partial correlation analysis also suggests that malaria, by itself, may exert opposite effects on thalassemia and G-6-PD selection. The present results support the hypothesis that thalassemia may be the primary genetic factor selected by malaria, whereas G-6-PD selection may be a secondary adaptation phenomenon strongly dependent on other genetic and environmental variables.     

Disruption of calcitonin gene-related peptide signaling accelerates muscle denervation and dampens cytotoxic neuroinflammation in SOD1 mutant mice

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. Neuronal vacuolization and glial activation are pathologic hallmarks in the superoxide dismutase 1 (SOD1) mouse model of ALS. Previously, we found the neuropeptide calcitonin gene-related peptide (CGRP) associated with vacuolization and astrogliosis in the spinal cord of these mice. We now show that CGRP abundance positively correlated with the severity of astrogliosis, but not vacuolization, in several motor and non-motor areas throughout the brain. SOD1 mice harboring a genetic depletion of the βCGRP isoform showed reduced CGRP immunoreactivity associated with vacuolization, while motor functions, body weight, survival, and astrogliosis were not altered. When CGRP signaling was completely disrupted through genetic depletion of the CGRP receptor component, receptor activity-modifying protein 1 (RAMP1), hind limb muscle denervation, and loss of muscle performance were accelerated, while body weight and survival were not affected. Dampened neuroinflammation, i.e., reduced levels of astrogliosis in the brain stem already in the pre-symptomatic disease stage, and reduced microgliosis and lymphocyte infiltrations during the late disease phase were additional neuropathology features in these mice. On the molecular level, mRNA expression levels of brain-derived neurotrophic factor (BDNF) and those of the anti-inflammatory cytokine interleukin 6 (IL-6) were elevated, while those of several pro-inflammatory cytokines found reduced in the brain stem of RAMP1-deficient SOD1 mice at disease end stage. Our results thus identify an important, possibly dual role of CGRP in ALS pathogenesis.