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PubMed2006

Psychological consequences of prenatal diagnosis in a case of familial Angelman syndrome.

Angelman Syndrome (AS), characterized by mental retardation, absence of speech, seizures and motor dysfunction, is caused by genetic defects leading to loss of expression of the maternal copy of the chromosome 15q11-13 imprinted region. Most cases are sporadic, being caused by de novo deletion of maternal chromosome 15q11-13 (75%) or by paternal uniparental disomy (3-4%). Familial cases can occur, due to mutations in the UBE3A gene or in the imprinting center. We describe the case of a pregnant woman having two nephews with AS caused by a UBE3A mutation; lack of communication within the family led the woman to be completely unaware of the risk of disease recurrence until 15 weeks of gestation. UBE3A genetic testing revealed she carried the familial mutation 892-893delCT. Prenatal diagnosis was performed on amniotic fluid and demonstrated that the fetus had inherited the mutation. The unexpected diagnosis and the subsequent termination of the pregnancy caused the woman to undergo acute psychological distress showing relevant psychopathological symptoms. Nevertheless, at 2-year follow-up, adverse consequences were minimized, and the couple was planning a new pregnancy. Factors affecting the psychological outcome of abortion and the role of psychological support in reducing the risk of long-term unfavorable consequences are discussed.

Abortion, Induced↗
PubMed2005

Frequency of potential azole drug-drug interactions and consequences of potential fluconazole drug interactions.

PURPOSE: To assess the frequency of potential azole-drug interactions and consequences of interactions between fluconazole and other drugs in routine inpatient care. METHODS: We performed a retrospective cohort study of hospitalized patients treated for systemic fungal infections with an oral or intravenous azole medication between July 1997 and June 2001 in a tertiary care hospital. We recorded the concomitant use of medications known to interact with azole antifungals and measured the frequency of potential azole drug interactions, which we considered to be present when both drugs were given together. We then performed a chart review on a random sample of admissions in which patients were exposed to a potential moderate or major drug interaction with fluconazole. The list of azole-interacting medications and the severity of interaction were derived from the DRUGDEX System and Drug Interaction Facts. RESULTS: Among the 4,185 admissions in which azole agents (fluconazole, itraconazole or ketoconazole) were given, 2,941 (70.3%) admissions experienced potential azole-drug interactions, which included 2,716 (92.3%) admissions experiencing potential fluconazole interactions. The most frequent interactions with potential moderate to major severity were co-administration of fluconazole with prednisone (25.3%), midazolam (17.5%), warfarin (14.7%), methylprednisolone (14.1%), cyclosporine (10.7%) and nifedipine (10.1%). Charts were reviewed for 199 admissions in which patients were exposed to potential fluconazole drug interactions. While four adverse drug events (ADEs) caused by fluconazole were found, none was felt to be caused by a drug-drug interaction (DDI), although in one instance fluconazole may have contributed. CONCLUSIONS: Potential fluconazole drug interactions were very frequent among hospitalized patients on systemic azole antifungal therapy, but they had few apparent clinical consequences.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Risks and consequences of gene flow from herbicide-resistant crops: canola (Brassica napus L) as a case study.

Data from the literature and recent experiments with herbicide-resistant (HR) canola (Brassica napus L) repeatedly confirm that genes and transgenes will flow and hybrids will form if certain conditions are met. These include sympatry with a compatible relative (weedy, wild or crop), synchrony of flowering, successful fertilization and viable offspring. The chance of these events occurring is real; however, it is generally low and varies with species and circumstances. Plants of the same species (non-transgenic or with a different HR transgene) in neighbouring fields may inherit the new HR gene, potentially generating plants with single and multiple HR. For canola, seed losses at harvest and secondary dormancy ensures the persistence over time of the HR trait(s) in the seed bank, and the potential presence of crop volunteers in subsequent crops. Although canola has many wild/weedy relatives, the risk of gene flow is quite low for most of these species, except with Brassica rapa L. Introgression of genes and transgenes in B rapa populations occurs with apparently little or no fitness costs. Consequences of HR canola gene flow for the agro-ecosystem include contamination of seed lots, potentially more complex and costly control strategy, and limitations in cropping system design. Consequences for non-agricultural habitats may be minor but appear largely undocumented.

Brassica napus↗
PubMed1990

Interaction of drugs with extranuclear genetic elements and its consequences.

Bacterial ancestry of mitochondria and plastids is now generally accepted. Both organelles contain their own DNA and transcription-translation apparatus of a prokaryotic type. Due to this fact these systems carry bacteria-like properties. Thus organellar DNA and ribosomes are essentially different from nuclear DNA and cytoplasmic ribosomes in physical as well as in functional respects. Due to the bacterial character of both types of organelles they are susceptible to various antibacterial chemicals. Inhibitors of bacterial protein synthesis inhibit mitochondrial (plastidial) biogenesis. Therefore the cellular content of mitochondria (plastids)-made proteins decreases during cytoplasmic turnover or cell division in the presence of these drugs. Such drug activity consequently leads to a reduced capacity for oxidative phosphorylation or photosynthesis. Organellar genomes are less stable and more sensitive to mutagenesis as compared to nuclear genome. It means also that genotoxic agents induce various disorders of mitochondrial (plastidial) functions. Impairments in the respiratory chain are associated with structural as well as functional abnormalities of mitochondria. These are clinically expressed mostly in tissues with a high demand for ATP: brain, heart, skeletal muscle, and retina. On the other hand, some antibacterial inhibitors of mitochondrial biogenesis (e.g., tetracyclines) inhibit selectively tumor cell proliferation. Therefore they may be considered for use in anticancer therapy. The article summarizes the response of mitochondria and plastids in various organisms to drugs and environmental xenobiotics. Various model organisms suitable for detection of xenobiotic effect on mitochondria (plastids) are presented as well as the possible consequences of such interaction.

Animals↗
PubMed1991

Physiological consequences of early neonatal growth retardation: effects of alpha-difluoromethylornithine on renal growth and function in the rat.

The physiological consequences of early neonatal growth retardation in the kidney were investigated using alpha-difluoromethylornithine (DFMO), a specific irreversible inhibitor of ornithine decarboxylase (ODC), a key enzyme in the biosynthesis of polyamines. We administered by s.c. 500 mg/kg/day DFMO, or saline, to Sprague-Dawley rat pups from the day of birth through postnatal day (PD) 6 and evaluated renal function on PD 4, 7, 10, and 13 using tests of basal renal clearance and urinary concentrating ability. Kidney weights and gross pathology were also obtained. On PD 39, serum chemistries and organ weights were determined. In a second experiment, we evaluated concentrating ability on PD 7-10, and basal renal function, concentrating ability, diuretic response, serum chemistries, and organ weights on PD 132-140. DFMO selectively inhibited renal growth but did not inhibit glomerular and tubular functional maturation. In fact, the rates of filtration and reabsorption (per g renal tissue), and concentrating ability were increased in treated pups. These changes were associated with long-term effects on renal function, including uremia, glucosuria, and male-specific concentrating deficits in adulthood. Several hypotheses can be developed concerning the physiological mechanisms underlying these changes (e.g., altered renal urea metabolism), which in turn may reflect either a direct role of ODC in the regulation of maturation or secondary consequences of inhibition of ODC.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1998

Causes and consequences of natal dispersal in root voles, Microtus oeconomus.

To test the causes and consequences of variation in natal dispersal in root voles we released 53 matrilines (mothers with newly weaned litters) separately in field enclosures, during nine consecutive periods. The matrilines could disperse and distribute themselves among three pre-emptied habitat patches. Two dispersal measures were recorded: short-distance dispersal defined as individuals immigrating to a neighbouring patch, and long-distance dispersal defined as unsettled individuals captured along the fence of the enclosures. We analysed the role of social factors (i.e. maternal and litter characteristics), habitat quality (i.e. seasonal effect) and experimentally manipulated shape of the natal patch in dispersal. The consequences of dispersal were analysed with respect to the spatial distribution of kin, and to pregnancy in females and sexual maturation in males. Dispersal was unrelated to patch shape. In agreement with the inbreeding avoidance hypothesis, long-distance dispersal was male biased and philopatric males were most frequently reproductively inactive. Whilst young males avoided their mother, they seemed to disperse, settle and mature sexually independently of their sisters. In agreement with the resource competition hypothesis, young females avoided their mother and were most frequently reproductively inactive when residing in their mother's patch. We conclude that inbreeding avoidance was underlying the male dispersal pattern. For females, long-distance dispersal was most in agreement with the inbreeding avoidance hypothesis while short-distance dispersal could be explained by the resource competition hypothesis. (c) 1998 The Association for the Study of Animal Behaviour.

Journal Article↗
PubMed1999

Metabolic consequences of agonistic behaviour: crab fights in declining oxygen tensions.

The energetic consequences of fighting, which may depend on environmental conditions, can be an important factor shaping contest strategy and duration. Energy expenditure may be costly to fitness because it depletes reserves that could otherwise have been allocated to reproduction, and metabolites are produced that may constrain subsequent activities. We examined the variation in the metabolic consequences of fighting in relation to hypoxia. Contests were staged between pairs of size-matched male shore crabs Carcinus maenas L., under a range of water oxygen tensions (between 10 and 100% oxygen saturation) which crabs experience in their natural habitat. Fighting under normoxic and hypoxic conditions resulted in significantly elevated concentrations of haemolymph metabolites (L-lactate and glucose) compared with crabs at rest. However, these concentrations were much lower than in crabs that had been walking on a treadmill. Glycogen concentrations differed only under hypoxic conditions: glycogen stores were reduced in crabs after fighting and this reduction was similar to that after exercise on a treadmill. Contests were shorter when they were staged below a water P o2of 6.7 kPa ( approximately 30% normoxia). As water oxygen tensions were reduced, fighting crabs had greater concentrations of L-lactate and glucose in their blood and tissues whilst glycogen stores were reduced. Fights became shorter when crabs were exposed to severe hypoxia (P o2=2 kPa) for increasing lengths of time, and blood L-lactate concentrations increased. The results suggest that as fights progressed, crabs experienced an increasing metabolic debt, in the form of accumulation of L-lactate and a reduction in energy stores, which was amplified by hypoxic conditions. Copyright 1999 The Association for the Study of Animal Behaviour.

Journal Article↗
PubMed1996

Engagement in Academic Work: The Role of Learning Goals, Future Consequences, Pleasing Others, and Perceived Ability

Engagement in academic work was viewed from a multiple goals perspective. Two studies were conducted in which high school math students completed an instrument measuring five goals students might have for doing academic work (learning goals, performance goals, obtaining future consequences, pleasing the teacher, and pleasing the family), perceived math ability, self-regulatory activities, strategies (deep or shallow) used when studying for math, and the amount of effort and persistence expended on the class. Factor analysis indicated that the five goals scales and the perceived ability scale represented unique factors. The correlations among the variables revealed theoretically consistent interrelationships. Multiple regression analyses indicated that various goals (e.g., learning goals, obtaining future consequences, and pleasing the teacher), perceived ability, and some interactions accounted for significant amounts of variance in the task engagement measures (self-regulation, strategy use, effort, and persistence) and achievement. Results are discussed in relation to current theory and their practical implications.

Journal Article↗
PubMed2001

Positive and negative consequences of soluble Fas ligand produced by an antigen-specific CD4(+) T cell response in human carcinoma immune interactions.

The influence of a human CD4(+) T cell response in anti-carcinoma immune reactions remains largely uncharacterized. Here, we made use of a major histocompatibility complex (MHC) class-II-restricted, anti-ras oncogene-specific CD4(+) T cell line produced previously in vivo from a patient with metastatic carcinoma in a peptide-based phase I trial. Using this patient-derived T cell line as a potentially relevant cell type, we examined the consequences of the anti-carcinoma CD4(+) T cell response, with emphasis on specific lymphokines potentially important for the regulation of Fas/Fas ligand (FasL) interactions. Antigen (Ag)-specific CD4(+) T cells produced substantial amounts of IFN-gamma following recognition of MHC class-II-matched Ag-presenting cells expressing the cognate peptide. The IFN-gamma promoted significant upregulation of Fas on the surface of colon carcinoma cells and sensitized these targets to Fas-mediated apoptosis and Ag-specific CD8(+) cytotoxic T lymphocyte (CTL)-mediated lysis involving a Fas-based effector mechanism. Moreover, Ag-stimulated CD4(+) T cells secreted soluble FasL (sFasL), which induced the death of TNF-resistant/refractory colon, breast, and ovarian carcinoma cells. Interestingly, although CD4(+)-derived sFasL expressed cytotoxic activity, the recovery of carcinoma cells which resisted Fas-mediated lysis displayed enhanced metastatic ability in vivo, compared with the unselected parental population, in an athymic mouse model. Thus, a tumor-specific CD4(+) T cell response may have both positive and negative consequences in human carcinoma via the production of proinflammatory cytokines such as IFN-gamma and/or sFasL that may (1) improve or facilitate CTL-target engagement, contact-independent effector mechanisms, and the overall lytic outcome and (2) potentially select for Fas-resistant tumor cells that escape immune destruction, which may thus impact the metastatic process.

CD4-Positive T-Lymphocytes↗
PubMed1997

Modeling T-cell proliferation: an investigation of the consequences of the Hayflick limit.

Somatic cells, including immune cells such as T-cells have a limited capacity for proliferation and can only replicate for a finite number of generations (known as the Hayflick limit) before dying. In this paper we use mathematical models to investigate the consequences of introducing a Hayflick limit on the dynamics of T-cells stimulated with specific antigen. We show that while the Hayflick limit does not alter the dynamics of T-cell response to antigen over the short term, it may have a profound effect on the long-term immune response. In particular we show that over the long term the Hayflick limit may be important in determining whether an immune response can be maintained to a persistent antigen (or parasite). The eventual outcome is determined by the magnitude of the Hayflick limit, the extent to which antigen reduces the input of T-cells from the thymus, and the rate of antigen-induced proliferation of T-cells. Counter to what might be expected we show that the persistence of an immune response (immune memory) requires the density of persistent antigen to be less than a defined threshold value. If the amount of persistent antigen (or parasite) is greater than this threshold value then immune memory will be relatively short lived. The consequences of this threshold for persistent mycobacterial and HIV infections and for the generation of vaccines are discussed.

Antigens↗
PubMed2002

Linking actions and their perceivable consequences in the human brain.

Voluntary action is goal-directed and therefore depends on the ability to learn associations between movements and their perceivable consequences. The neural substrate of this ability was investigated with H2(15O) positron emission tomography (PET). Healthy adults first learned that self-initiated keypresses were consistently followed by certain tones (i.e., action effects). During PET imaging, participants listened to varied ratios of action-effect tones and neutral tones without performing any movement. The caudal supplementary motor area and the right hippocampus increased their activity with the frequency of action-effect tones, suggesting that both cortical areas play a role in linking the consequences of an action and the action itself. This integration process represents a highly flexible mechanism that helps to promote the learning, automatization, and control of voluntary

Acoustic Stimulation↗
PubMedDate not supplied

Trends in tobacco smoking and consequences on health in France.

OBJECTIVE: This paper describes the trends in tobacco sales and smoking prevalence in the French population, estimates the consequences of smoking on the mortality of this population, and discusses governmental actions: anti-tobacco campaigns, a ban on advertising, restriction of smoking in public places, and price increases. DATA SOURCES: Sales data were collected from the French tobacco monopoly, smoking prevalence data from surveys conducted by several institutes, and mortality statistics by cause from the Institut National de la Santé et de la Recherche Médicale. RESULTS: Tobacco sales increased from 3 g per adult per day at the beginning of the century to a maximum of 6.8 g in 1975, then decreased by 10% between 1991 and 1996. Since the early 1950s, the proportion of smokers has been on the decline in the male population and on the increase in the female population. In France, 60,000 deaths are attributable to tobacco smoking. These deaths represent 12% of the total mortality. The advertising ban has been enforced and the recent price increase has led to a drop in sales. CONCLUSIONS: The consequences of tobacco smoking on the health of the female French population will increase for another 30 years, because of the increase in female smoking observed in the recent past, whereas the epidemic is leveling off in the male population.

Adult↗
PubMed1999

M cells as ports of entry for enteroinvasive pathogens: mechanisms of interaction, consequences for the disease process.

M cells are key sites of antigen sampling for the mucosal-associated lymphoid system (MALT) and consequently are essential components of the structures serving as inductive sites for mucosal immunity. In addition, they have recently been recognized as major sites of adherence and major ports of entry for enteric pathogens. In the case of enteroinvasive pathogens, such as Salmonella, Yersinia and Shigella, few clinical evidences, but lots of experimental data indicate that, at least at the early stage of infection, M cells of the follicular associated epithelium transport the pathogens. This has significantly altered our view on the pathogenesis of enteroinvasive infections. Crossing the epithelial barrier seems an achievable task for these bacteria which express adherence and invasion mechanisms which have often been well characterized in epithelial cell lines. These systems seem to be also used for entering and crossing M cells, although reproducible in vitro assays for M cell infection are now required. Having crossed the epithelial lining, the bacteria face phagocytic cells, particularly the macrophages that are present in the follicle dome. Depending on the capacity to survive in the presence of macrophages, and how this survival is achieved by a given invasive species, the outcome of infection can be dramatically affected. In consequence, M cells can be considered as pathogen translocators toward immunocompetent areas of the gut, thus opening the possibility to harness this property in order to design new mucosal vaccines or vaccine vectors.

Antigens↗
PubMed2002

Reduced antigenicity of the hepatitis B virus HBsAg protein arising as a consequence of sequence changes in the overlapping polymerase gene that are selected by lamivudine therapy.

The prevalence of hepatitis B virus vaccine escape mutants has increased as a consequence of the introduction of global vaccination programs. Furthermore and as a consequence of the organization of the genome of hepatitis B virus (HBV) into overlapping reading frames, the selection of polymerase mutants during long-term lamivudine therapy can select viruses with changes in the overlapping S gene coding for the hepatitis B small antigen (HBsAg). We have investigated the role of lamivudine in selecting HBV mutants with antigenically altered HBsAg protein using pooled human vaccine sera in enzyme immunosorbent assays and radioimmunoassays. HBsAg proteins containing the vaccine escape mutations G145R and D144E/G145R demonstrated markedly reduced binding to anti-HBs antibody. HBsAg mutants including E164D, W196S, I195M, M198I, and E164D/I195M (corresponding to the polymerase protein changes of V519L, M550I, L526M/M550V V553I, and V519L/L526M/M550V) selected during lamivudine treatment also demonstrated reduced binding to anti-HBs antibody. These findings raise the possibility of lamivudine-resistant mutants arising that possess antigenically distinct HBsAg proteins.

DNA-Directed DNA Polymerase↗
PubMed1995

Mental and physical health consequences of alcohol use in women.

Chronic consumption of alcohol in levels typically consumed by alcoholic women clearly produces adverse health consequences, including a shorter life expectancy. The health consequences of alcohol use appear to depend on the characteristics of the person consuming the alcohol (genetic vulnerability to particular diseases, the particular point in the life span when the majority of the alcohol is consumed, and the pattern of consumption typical for that individual). For adolescence and young adulthood, emphasis is placed on increased rates of accidental and suicidal mortality. For middle age, breast cancer risk and risk for developing osteoporosis is discussed. Finally, use of alcohol alone and in combination with psychoactive drugs presents special problems for older women. Other specific adverse effects of alcohol are reviewed with respect to gender differences in cardiovascular, hepatological, and neuropathological outcome, as well as with respect to HIV/AIDS. Psychiatric comorbidity and domestic violence are also discussed with respect to gender differences.

Adolescent↗
PubMed2005

Adolescent alcohol drinking and its long-range consequences. Studies with animal models.

This chapter reviews findings, mainly obtained from the selectively bred alcohol-preferring (P) line of rats, on (a) the development of alcohol drinking during the peri-adolescent period, (b) neurobiological factors that may contribute to adolescent drinking, (c) interventions to prevent alcohol drinking during adolescence, and (d) some long-lasting consequences of adolescent alcohol drinking. The findings indicate that P rats readily initiate alcohol drinking during the early post-weaning, adolescent and peri-adolescent periods of development. The early age-of-onset of alcohol drinking in the P compared to the NP line is associated with (a) higher densities of serotonin-1A (5-HT1A) receptors in cerebral cortical and hippocampal regions; (b) lower densities of dopamine (DA) D2 receptors in the ventral tegmental area (VTA); (c) higher functional activity in several limbic, cortical and hippocampal regions; and (d) sensitivity to the low-dose stimulating effect of ethanol. Conditioned taste aversion (CTA) training during adolescence produces long-term effects on preventing high alcohol drinking behavior of P rats. Alcohol drinking during peri-adolescence by P rats produces long-lasting effects that increase the acquisition of ethanol self-administration in adulthood, and, in addition, increase craving-like behavior and the potential for alcohol relapse. With suitable animal models, a better understanding of the mechanisms underlying adolescent alcohol drinking and its long-range consequences can be attained.

Adolescent↗
PubMed1990

Lead exposure in early life: health consequences.

Until very recently it has been considered that of the many manifestations of lead toxicity, those involving the elaboration and function of hemoproteins occur at lower levels of lead exposure than any others. The critical target seems to be the enzyme heme synthetase, which is essential for the insertion of iron into the precursor, protoporphyrin IX. The major consequences of this effect, which have been evaluated in both adults and children, are reduction of circulating levels of hemoglobin and cytochrome P-450-dependent Phase I drug metabolism. Lead clearly inhibits normal hemoprotein function in both respects. The threshold level of lead exposure for these effects seems to be at a circulating lead concentration (PbB) of approximately 30 to 40 micrograms/dL. A growing body of evidence suggests, however, that the functional integrity of the central nervous system is compromised at substantially lower levels of lead exposure, particularly in the human fetus and young child. Early postnatal neurobehavioral development is compromised at maternal or cord PbB of somewhat less than approximately 10 micrograms/dL, a level of lead exposure not uncommon in the general population. Results of more recent cross-sectional and prospective studies indicate that postnatal lead exposure resulting in PbBs as low as 25 micrograms/dL, and probably lower, also are associated with deficits in intellectual attainment, achievement, and behavior. The long-term consequences of these effects remain to be fully evaluated. Little is known concerning basic mechanisms that are responsible for these effects. They may be manifestations of a more basic common effect of lead on cell proliferation and differentiation.

Adult↗
PubMed1987

Chronic cardiac reactions. II. Mechanical and energetic consequences of myocardial transformation versus ventricular dilatation in the chronically pressure-loaded heart.

Mechanical and energetic consequences of myocardial transformation and of ventricular configuration on the other were separately analysed. The considerations were realized on representative samples of normotensive rats and spontaneously hypertensive rats (SHR) in compensated stages, as well as in SHR in a state of congestive cardiac failure. Cardiac dynamic measurements were performed under Urethane anaesthesia and open chest conditions. Myosin isoenzyme pattern was determined by pyrophosphate gel electrophoresis. Energetic calculations were based on oxygen consumption data, measured in a specified heart-lung model. In the compensated stage of SHR the concentric type of left ventricular hypertrophy with renormalized systolic auxotonic wall stress predominated. The process of cardiac hypertrophy was associated with a shift in the myosin isoenzyme pattern towards the "slow" VM-3. Myocardial transformation did not significantly reduce myocardial performance and pumping ability, but caused a decrease in oxygen consumption as related to developed stress and LV weight. Thus, the efficiency of the hypertrophied ventricle of SHR was improved. However, due to the moderate effect of isoenzyme pattern redistribution for total energy turnover and the limited adaptive reserve of normotensive controls, the extent of improvement was small. In SHR with congestive heart failure, myocardial contractility was severely impaired, when structural dilatation of the left ventricle had set in. Reduced myocardial contractility could not be explained solely on the basis of a shift in the myosin isoenzyme pattern. Both impaired myocardial contractility and structural dilatation contributed to reduced ventricular performance. Myocardial transformation, along with its energy economizing effect, failed to compensate for unfavorable energetic consequences of structural dilatation and therefore the reduced ventricular efficiency is assumed to be another deleterious factor in the dilated failing heart.

Animals↗