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PubMed2002

Prediction of outcomes in hypertensive patients with suspected coronary disease.

Stress echocardiography has been shown to improve the diagnosis of coronary artery disease in the presence of hypertension, but its value in prognostic evaluation is unclear. We sought to determine whether stress echocardiography could be used to predict mortality in 2363 patients with hypertension, who were followed for up to 10 years (mean 4.0+/-1.8) for death and revascularization. Stress echocardiograms were normal in 1483 patients (63%), 16% had resting left ventricular (LV) dysfunction alone, and 21% had ischemia. Abnormalities were confined to one territory in 489 patients (21%) and to multiple territories in 365 patients (15%). Cardiac death was less frequent among the patients able to exercise than among those undergoing dobutamine echocardiography (4% versus 7%, P< 0.001). The risk of death in patients with a negative stress echocardiogram was <1% per year. Ischemia identified by stress echocardiography was an independent predictor of mortality in those able to exercise (hazard ratio 2.21, 95% confidence intervals 1.10 to 4.43, P=0.0001) as well as those undergoing dobutamine echo (hazard ratio 2.39, 95% confidence intervals 1.53 to 3.75, P=0.0001); other predictors were age, heart failure, resting LV dysfunction, and the Duke treadmill score. In stepwise models replicating the sequence of clinical evaluation, the results of stress echocardiography added prognostic power to models based on clinical and stress-testing variables. Thus, the results of stress echocardiography are an independent predictor of cardiac death in hypertensive patients with known or suspected coronary artery disease, incremental to clinical risks and exercise results.

Cohort Studies↗
PubMed1998

Induction of DNA fragmentation and HSP72 immunoreactivity by adenovirus-mediated gene transfer in normal gerbil hippocampus and ventricle.

Foreign genes have been successfully transferred and expressed in experimental animal brains using adenoviral vectors. However, it is not fully understood whether adenovirus-mediated gene transfer causes stressful or cytotoxic injury in brain. A replication-defective adenoviral vector containing the Escherichia coli lacZ gene (AdCMVnLacZ) was directly injected into right hippocampus and lateral ventricle of normal gerbil brains. Temporal and spatial profiles of the expression of lacZ gene products, DNA fragmentation detected by terminal deoxynucleotidyl d-UTP nick end labeling (TUNEL) staining, and heat shock protein 72 (HSP72) immunoreactivity were examined until 21 days after the injection. In the ventricle, lacZ gene was immediately and strongly expressed at 8 hr after the injection of AdCMVnLacZ, with a peak at 1-3 days, and disappeared by 21 days. Although a small number of choroid plexus cells were TUNEL positive at 3 and 7 days, no HSP72 immunostaining was observed in the ventricle. Small-to-moderate expression of lacZ gene was found in the needle route from 8 hr to 3 days after the injection, and a small number of TUNEL-positive cells were detected at the needle track at 1-3 days. In the hippocampus, lacZ gene was markedly expressed around the dentate gyrus (DG) at 8 hr to 3 days with a peak at 1 day. Large number of TUNEL or moderate-to-dense HSP70 staining cells were also detected in the same area. CA1 neuronal cells just adjacent to the needle route showed TUNEL positivity at 1 to 3 days. However, the TUNEL staining was not associated with lacZ gene expression. The majority of lacZ-expressing cells were discriminated from the TUNEL-positive cells, whereas some were double-positive with HSP72 staining in DG. Cellular loss was observed in the CA1 layer around the needle route. An apoptotic change was morphologically observed in the marginal region of the DG at 1-3 days and in the ventricle at 3-7 days. In the sham control group, TUNEL-positive or HSP72-staining cells were only detected around the needle track including CA1 cells adjacent to the needle route. These data suggest that adenoviral gene transfer may induce direct traumatic injury in the CA1 sector near the needle route, indirect apoptotic cell loss in the DG and ventricle, and stressful effect on the dentate granule cells in association with adenovirus infection in normal gerbil brain.

Adenoviridae↗
PubMed2006

8-Oxo-7,8-dihydro-2'-deoxyguanosine is not salvaged for DNA synthesis in human leukemic U937 cells.

8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG), the most common oxidatively modified nucleoside, is released from oxidized DNA and oxidized nucleotide pool. However, little information is available regarding the metabolic pathway of free 8-oxo-dG. In this study, we generated radiolabeled 8-oxo-dG to track its metabolic fate. We report that 8-oxo-dG is neither phosphorylated to 8-oxo-dGMP nor degraded to the free base, 8-oxo-7,8-dihydroguanine (8-oxo-Gua), indicating that 8-oxo-dG is not a substrate for nucleotide synthesis. This result was confirmed by the finding that no radioactivity was detected in the DNA of U937 cells after incubating the cells with radiolabeled 8-oxo-dG. These observations indicate that 8-oxo-dG produced by oxidative stress is not reutilized for DNA synthesis.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2007

Ribonucleotide reductase and the regulation of DNA replication: an old story and an ancient heritage.

All organisms that synthesize their own DNA have evolved mechanisms for maintaining a constant DNA/cell mass ratio independent of growth rate. The DNA/cell mass ratio is a central parameter in the processes controlling the cell cycle. The co-ordination of DNA replication with cell growth involves multiple levels of regulation. DNA synthesis is initiated at specific sites on the chromosome termed origins of replication, and proceeds bidirectionally to elongate and duplicate the chromosome. These two processes, initiation and elongation, therefore determine the total rate of DNA synthesis in the cell. In Escherichia coli, initiation depends on the DnaA protein while elongation depends on a multiprotein replication factory that incorporates deoxyribonucleotides (dNTPs) into the growing DNA chain. The enzyme ribonucleotide reductase (RNR) is universally responsible for synthesizing the necessary dNTPs. In this review we examine the role RNR plays in regulating the total rate of DNA synthesis in E. coli and, hence, in maintaining constant DNA/cell mass ratios during normal growth and under conditions of DNA stress.

DNA Replication↗
PubMed2000

Nitric oxide induced expression of stress proteins in virulent and avirulent promastigotes of Leishmania donovani.

Intracellular survival and replication of Leishmania donovani inside macrophage is essential for establishment of the disease. Cytokines play an important role in this process through activation or inhibition of macrophage antimicrobial activity. Nitric oxide (NO) has been demonstrated to be the principal effector molecule mediating intracellular killing of Leishmania. We have examined the effect of NO and various other cytokines on stress protein synthesis by promastigotes of L. donovani virulent and avirulent strains. Virulent promastigotes exposed to NO showed appreciable increase in relative synthesis of HSPs 83, 70 and 65. The overexpression of HSPs on exposure of parasite to NO was observed to be more pronounced at 37 degrees C than at 24 degrees C. In contrast, the avirulent promastigotes responded by an increase in relative synthesis of HSP70 alone at 37 degrees C. Furthermore, treatment of promastigotes of L. donovani with gammaIFN, TGF-beta or IL-4 did not significantly alter the stress proteins expression. The overexpression of HSPs in promastigotes of L. donovani in response to sublethal doses of NO suggests that HSPs may be playing a protective role for parasite survival in the mammalian host. This is further supported by the observation that a significantly higher induction of HSPs is seen in the virulent as compared to the avirulent strain of L. donovani.

Amino Acid Sequence↗
PubMed2005

Overexpressed Sod1p acts either to reduce or to increase the lifespans and stress resistance of yeast, depending on whether it is Cu(2+)-deficient or an active Cu,Zn-superoxide dismutase.

Yeast overexpressing SOD1, the gene for Cu,Zn-superoxide dismutase (Cu,Zn-Sod), was used to determine how Sod1p overexpression influences the chronological lifespan [the survival of non-dividing stationary (G0) phase cells over time], the replicative lifespan (the number of buds produced by actively dividing yeast cells) and stress resistance. Increasing the level of active Cu,Zn-Sod in yeast was found to require either growth in the presence of high copper, or the simultaneous overexpression of both SOD1 and CCS1 (the latter being the gene that encodes the chaperone dedicated to Cu(2+)-loading of Sod1p in vivo). Dual SOD1 + CCS1 overexpression elevated the levels of Cu,Zn-Sod activity six- to eight-fold in vegetative cultures. It also increased the optimized survival of stationary cells up to two-fold, showing this chronological lifespan is ultimately limited by oxidative stress. In contrast, several detrimental effects resulted when the SOD1 gene was overexpressed in the absence of either high copper or a simultaneous overexpression of CCS1. Both the chronological and the replicative lifespans were shortened; the cells displayed an abnormally high level of endogenous oxidative stress, resulting in a high rate of spontaneous mutation. Such harmful effects were all reversed through the overexpression of CCS1. It is apparent therefore that they relate to the incomplete Cu(2+)-loading of the overexpressed Sod1p, most probably accumulation of a Cu(2+)-deficient Sod1p to appreciable levels in vivo. The same events may generate the detrimental effects that are frequently, though not universally, observed when Cu,Zn-Sod overexpression is attempted in metazoans.

Catalase↗
PubMed1999

The mutagenesis protein UmuC is a DNA polymerase activated by UmuD', RecA, and SSB and is specialized for translesion replication.

Replication of DNA lesions leads to the formation of mutations. In Escherichia coli this process is regulated by the SOS stress response, and requires the mutagenesis proteins UmuC and UmuD'. Analysis of translesion replication using a recently reconstituted in vitro system (Reuven, N. B., Tomer, G., and Livneh, Z. (1998) Mol. Cell 2, 191-199) revealed that lesion bypass occurred with a UmuC fusion protein, UmuD', RecA, and SSB in the absence of added DNA polymerase. Further analysis revealed that UmuC was a DNA polymerase (E. coli DNA polymerase V), with a weak polymerizing activity. Upon addition of UmuD', RecA, and SSB, the UmuC DNA polymerase was greatly activated, and replicated a synthetic abasic site with great efficiency (45% bypass in 6 min), 10-100-fold higher than E. coli DNA polymerases I, II, or III holoenzyme. Analysis of bypass products revealed insertion of primarily dAMP (69%), and to a lesser degree dGMP (31%) opposite the abasic site. The UmuC104 mutant protein was defective both in lesion bypass and in DNA synthesis. These results indicate that UmuC is a UmuD'-, RecA-, and SSB-activated DNA polymerase, which is specialized for lesion bypass. UmuC is a member of a new family of DNA polymerases which are specialized for lesion bypass, and include the yeast RAD30 and the human XP-V genes, encoding DNA polymerase eta.

Bacterial Proteins↗
PubMedDate not supplied

Carotid baroreflex sensitivity at rest and during psychological stress in offspring of hypertensives and non-twin sibling pairs.

The baroreceptor reflexes of 38 young adult males were mechanically stimulated by negative external cervical pressure during a mental arithmetic task and pre-stress and post-stress relaxation periods. The subjects comprised 19 pairs of non-twin siblings. Baroreflex sensitivity was significantly less pronounced during arithmetic. Using non-invasive techniques, this finding replicates several others indicating a damping of the baroreceptor reflux during stress. More importantly, analyses of sibling similarities also revealed significant familiality of baroreflex sensitivity, independent of age, body mass, pressure applied and baseline heart rate. To examine the relationship between baroreflex sensitivity and parental history of hypertension, 21 young adult males with a parental history and 25 without participated in a second experiment. The two groups were not significantly different in resting baroreflex sensitivity. However, sensitivity was damped to a significantly greater degree during mental arithmetic in offspring of hypertensives, offering one possible explanation for their greater blood pressure reactivity to stress. These results suggest that familial influences may effect baroreflex sensitivity and, possibly as a result, blood pressure reactivity and risk for hypertension.

Adult↗
PubMed2002

Overexpression of apolipoprotein J in human fibroblasts protects against cytotoxicity and premature senescence induced by ethanol and tert-butylhydroperoxide.

Human diploid fibroblasts (HDFs) exposed to subcytotoxic stresses under H2O2, tert-butylhydroperoxide (t-BHP), and ethanol (EtOH) undergo stress-induced premature senescence (SIPS) characterized by many biomarkers of HDFs replicative senescence. Among these biomarkers are a growth arrest, an increase in the senescence-associated beta-galactosidase activity, a senescent morphology, an overexpression of p21waf-1 and the subsequent inability to phosphorylate pRb, the presence of the common 4977-bp mitochondrial deletion, and an increase in the steady-state level of several senescence-associated genes such as apolipoprotein J (apo J). Apo J has been described as a survival gene against cytotoxic stress. In order to study whether apo J would be protective against cytotoxicity SIPS and replicative senescence in human fibroblasts, a full-length complementary deoxyribonucleic acid of apo J was transfected into WI-38 HDFs and SV40-transformed WI-38 HDFs. The overexpression of apo J resulted in an increased cell survival after t-BHP and EtOH stresses at cytotoxic concentrations. In addition, when WI-38 HDFs were exposed to 5 subcytotoxic stresses with EtOH or t-BHP, in conditions that were previously shown to induce SIPS, a lower induction of 2 biomarkers of SIPS was observed in HDFs overexpressing apo J. No effect of apo J overexpression was observed on the proliferative life span of HDFs, even if apo J overexpression triggered osteonectin (SPARC) overexpression, which was shown to decrease the mitogenic potential of platelet-derived growth factor but not of other common growth-inducing conditions. Apo J senescence-related overexpression is proposed to have antiapoptotic rather than antiproliferative effects.

Cell Line, Transformed↗
PubMedDate not supplied

Blood lipids and lipoproteins in married and formerly married women.

As part of the Cardiovascular Occupational Risk Factors Determination in Israel (CORDIS) study, the association between marriage termination (divorce/separation or widowhood) and blood lipids and lipoproteins was examined in a sample of 351 healthy women employed in industry. Eighty-seven former spouses were each matched with three married women (N = 264) for age, number of children, smoking status, and type of job (blue/white collar). After controlling for age, number of cigarettes per day, leisure sport participation, and daily coffee consumption, former spouses in the younger women group (younger than 45 years) had significantly higher total cholesterol, total cholesterol ratio, and LDL levels than married women. Among older women (> or = 45 years), there were no significant differences. Significantly more younger former spouses had abnormally high cholesterol and LDL levels. In both age groups, former spouses smoked more cigarettes daily. These differences between the marital status groups may be explained by stress effects and changes in primary prevention practices. If replicated, such findings would delineate a population in need of intervention to reduce disease risk.

Adult↗
PubMed2003

Fitness and adaptation in a novel environment: effect of inbreeding, prior environment, and lineage.

The ability of populations to undergo adaptive evolution depends on the presence of genetic variation for ecologically important traits. The maintenance of genetic variation may be influenced by many variables, particularly long-term effective population size and the strength and form of selection. The roles of these factors are controversial and there is very little information on their impacts for quantitative characters. The aims of this study were to determine the impacts of population size and variable versus constant prior environmental conditions on fitness and the magnitude of response to selection. Outbred and inbred populations of Drosophila melanogaster were maintained under benign, constant stressful, and variably stressful conditions for seven generations, and then forced to adapt to a novel stress for seven generations. Fitness and adaptability were assayed in each replicate population. Our findings are that: (1) populations inbred in a variable environment were more adaptable than those inbred in a constant environment; (2) populations adapted to a prior stressful environment had greater fitness when reared in a novel stress than those less adapted to stress; (3) inbred populations had lower fitness and were less adaptable than the outbred population they were derived from; and (4) strong lineage effects were detectable across environments in the inbred populations.

Adaptation, Biological↗
PubMed1993

Influence of repeated restraint and isolation stress and electrolyte administration on pituitary-adrenal secretions, electrolytes, and other blood constituents of sheep.

Crossbred lambs (n = 24) were blocked by weight and assigned within blocks to four treatments applied in two replications of a 2 x 2 factorial arrangement. Main effects included no stress (NS) or three consecutive days of restraint and isolation stress (RIS) and treatment with either water (W) or an electrolyte (E) solution. Each lamb in the RIS treatment group was moved from its home stanchion to another room, isolated from visual and tactile contact with other lambs, and restrained for 6 h on three consecutive days. Lambs received either distilled W or E (320 mL) on each of the 3 d of stressor treatment. On the morning of the 3rd d of stressor treatment, blood samples were collected at 1-h intervals for 6 h for determination of concentrations of ACTH, cortisol, and lactate. Also, blood was collected at the conclusion of, and 18 h after, the termination of stressor treatment (at slaughter) to measure serum electrolyte concentrations and other blood constituents. Polynomial curves fit to plasma concentrations of ACTH, cortisol, and lactate data differed (P < .005) between RIS and NS lambs during the last 6-h stressor bout. Stressed lambs had lower (P < .05) serum calcium and alkaline phosphatase concentrations than did NS lambs. Serum glutamic oxaloacetic transaminase was increased (P < .05) 20- to 30-fold in RIS lambs. Restraint and isolation stress caused clear increases in plasma concentrations of ACTH, cortisol, lactate, and glutamic oxaloacetic transaminase but had minimal effects on serum electrolytes. Electrolyte treatment had no appreciable effect on pituitary-adrenal secretions or any other measured component of blood.

Adrenocorticotropic Hormone↗
PubMed1997

Analysis of expression and function of topoisomerase I and II during meiosis in male mice.

Topoisomerases are nuclear enzymes that remove torsional stress in DNA. Their function is important for replication, transcription, chromosome condensation, and chromosome segregation during mitosis and meiosis. The goal of this work is to analyze both expression and function of topoisomerases during the meiotic stages of mammalian spermatogenesis. The patterns of expression of topoisomerase I and topoisomerase II alpha genes were followed on Northern blots of RNA from testes of mice of different ages and from specific germ cell populations. The transcript of the topoisomerase I gene was highest in somatic cells of the testis and in the mitotically proliferating spermatogonia and meiotic prophase spermatocytes, with the level of transcript decreasing dramatically in postmeiotic spermatids. In contrast, the levels of topoisomerase II alpha transcript were negligible in germ-cell free testes and highest in late meiotic prophase cells and round spermatids. Enzyme activity for both topoisomerase I and topoisomerase II was detected in both pachytene spermatocytes and in round spermatids; topoisomerase II exhibited a higher level of activity in meiotic spermatocytes than in round spermatids. In cultured cells, camptothecin, an inhibitor of topoisomerase I, caused some abnormalities of paired meiotic homologs, but did not inhibit the transition to metaphase. In contrast, teniposide and ICRF-193, inhibitors of topoisomerase II, dramatically inhibited the formation of metaphase chromosomes in cells induced to progress from prophase to metaphase. However, the disassembly of the synaptonemal complex was not inhibited, indicating that this process could be uncoupled from condensation of chromatin to form chromosomes. These studies constitute evidence for a functional requirement for topoisomerase II activity in the transition from meiotic prophase to meiotic metaphase I in mammalian spermatocytes.

Animals↗
PubMed1998

Rorschach patterns of response in Vietnam veterans with posttraumatic stress disorder versus combat and normal controls.

To further evaluate Rorschach indicators of posttraumatic stress disorder (PTSD), test protocols of 16 combat veterans so diagnosed were compared with those of 9 combat controls and 12 noncombat subjects. Results replicated Rorschach abnormalities previously associated with this disorder, including signs of low stress tolerance, poor affect modulation, perceptual distortion, and interpersonal disengagement. However, only two indicators, EB (Erlebnistypus) and CC (combat-related content), differentiated PTSD subjects from controls (P < .05). Examination of negative findings revealed that all three groups similarly deviated from Exner nonpatient norms (Exner, 1993: The Rorschach, Vol 1. New York: John Wiley and Sons) on many Rorschach variables. Possible explanations for these findings are considered, and the need for control subjects in Rorschach investigation is underscored.

Adult↗
PubMed2003

Prolonged copper depletion induces expression of antioxidants and triggers apoptosis in SH-SY5Y neuroblastoma cells.

SH-SY5Y neuroblastoma cells were cultured for up to three serial passages in the presence of the copper chelator triethylene tetramine (Trien). The copper-depleted neuroblastoma cell line obtained showed decreased activities of the copper enzymes Cu, Zn super-oxide dismutase and cytochrome c oxidase with concomitant increases in reactive oxygen species. Mitochondrial antioxidants (Mn superoxide dismutase and Bcl-2)were up-regulated. Overexpression and activation of p53 were early responses, leading to an increase in p21. Eventually, copper-depleted cells detached from the monolayer and underwent apoptosis. Activation of upstream caspase-9, but not caspase-8, suggested that apoptosis proceeds via a mitochondrial pathway, followed by caspase-3 activation. The addition of copper sulfate to the copper-depleted cells restored copper enzymes, normalized antioxidant levels and improved cell viability. We conclude that prolonged copper starvation in these replicating cells leads to mitochondrial damage and oxidative stress and ultimately, apoptosis.

Antioxidants↗
PubMed2001

Molecular properties of Streptococcus thermophilus plasmid pER35 encoding a restriction modification system.

Bacteriophage attack on lactic fermentation bacteria (LFB) is costly to the dairy industry because it results in product loss. One mechanism used by LFB to protect themselves from bacteriophage attack is restriction of foreign DNA. Three plasmids, pER16, pER35, and pER36, from three different strains of the thermotolerant dairy fermentation bacterium Streptococcus thermophilus were sequenced. One of these plasmids, pER35, isolated from S. thermophilus ST135, encoded a type IC restriction-modification (R-M) system very similar to those encoded on plasmids pIL2614 in Lactococcus lactis subsp. lactis and pND861 in Lactococcus lactis biovar diacetylactis. The high degree of identity between the R-M systems encoded on pER35, pIL2614, and pND861 indicated the potential for horizontal transfer of these genes between different species of lactic fermentation bacteria. Similar to the functional R-M system encoded on pIL2614 that protects the mesophilic L. lactis subsp. lactis against phage attack, the R-M system on pER35 most likely functions in the same role in S. thermophilus ST135. The plasmid pER16 was found to encode the specificity subunit of the R-M system, but not the R or M subunits. In addition, all three plasmids encoded proteins that are present on other S. thermophilus plasmids, including a protein for rolling-circle replication (RepA) and a low-molecular-weight stress protein (Hsp). The presence of a complete R-M system encoded on a plasmid in S. thermophilus, a species that often lacks plasmids, is novel and may be beneficial for protecting S. thermophilus from bacteriophage attack under dairy fermentation conditions.

Amino Acid Sequence↗
PubMed2006

Conditional and replicative senescence in Escherichia coli.

Analysis of the molecular mechanisms underlying the cellular degeneration of bacteria in stationary phase (known as conditional senescence) reveals interesting similarities with the aging process of higher organisms. These similarities include the role of self-inflicted oxidative damage and the importance of protein quality control systems in retarding senescence. In addition, recent data suggests that Escherichia coli cells display signs of replicative senescence, or loss of fitness, during exponential growth and that this phenomenon targets the 'older' cells. Thus, bacterial physiology might entail both conditional and mandatory aging processes.

Adaptation, Physiological↗
PubMed2006

Restraint stress facilitates systemic dissemination of Theiler's virus and alters its pathogenecity.

Theiler's murine encephalomyelitis virus (TMEV), a Picornavirus used as a viral model for multiple sclerosis (MS), causes an acute encephalomyelitis and chronic demyelination. The failure to clear the virus, which can result from stress, is a prerequisite for development of the later disease. Similarly, stressful life events have been associated with the development of MS. In the present study, a restraint stress (RS) model was used to investigate the effect of stress on the systemic dissemination of TMEV during the early stage of disease. Experimental data demonstrated that repeated RS remarkably facilitated the spread of virus from the CNS to such systemic organs as the spleen, lymph nodes, thymus, lungs and heart and compromised the ability of viral clearance within those tissues. RS also altered the pathogenecity of TMEV, enabling it to become cardiotropic, resulting in higher myocardial infectivity. These results demonstrate the profound impact that RS has upon both the tissue and organ dissemination of the virus, and the organ tropism of TMEV. An additional finding associated with stress was hepatic necrosis in the restrained animals, regardless of whether or not they were infected.

Animals↗