Norwegian general population normative data for the European Organization for Research and Treatment of Cancer questionnaires: the Quality of Life Questionnaire-Core 30, the Sexual Health Questionnaire QLQ-SHQ22 and the sexual domains of the QLQ-BR23/BR45.

OBJECTIVE: The aim of this study was to provide sex-, age-, and morbidity-specific Norwegian general population normative values for the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires QLQ-C30, the sexual health questionnaire QLQ-SHQ22 and the sexual domains of the breast modules QLQ-BR23 and QLQ-BR45. METHODS: A random nationwide sample stratified by sex and age groups (18-29, 30-39, 40-49, 50-59, 60-69 and ≥70 years) was drawn from the Norwegian National Population Register. Participants were notified through national online health services (HelseNorge) and postal mail. The survey included sociodemographic background information, health-related quality of life assessed by the EORTC questionnaires, and morbidity assessed by the Self-Administered Comorbidity Questionnaire. Multivariable linear regression was carried out to estimate the associations of age, sex and morbidity with the EORTC scale and item scores. RESULTS: Of the 15,627 eligible individuals, 5135 (33%) responded. Women and persons with morbidities reported lower functioning and higher symptom burden than men and persons without morbidities, respectively, on nearly all EORTC scales. Sex differences were most prominent for emotional functioning, pain, fatigue and insomnia (QLQ-C30), body image, sexual functioning (QLQ-BR23/45), importance of sexual activity, libido and fatigue (QLQ-SHQ22). The score differences between persons with and without morbidity were highly significant and largest in the youngest and middle-aged groups. CONCLUSION: This is the first study to provide normative values for the EORTC sexual health questionnaire QLQ-SHQ22 and the sexual subscales of the QLQ-BR23 and QLQ-BR45 for all, separately in age groups by sex and morbidity.

Trait mindfulness and the mental and physical health of caregivers for individuals with cancer.

BACKGROUND: Mindfulness plays a role in moderating the negative mental and physical health outcomes associated with caregiving. The aims of this study were to examine the relationship between trait mindfulness and the (1) psychological functioning, (2) health behaviors, (3) and physical health of caregivers for individuals diagnosed with cancer. METHODS: Caregivers completed a battery of questionnaires and examinations assessing sociodemographic characteristics, trait mindfulness, depression, perceived stress, caregiver stress, sleep, diet, physical activity, tobacco use, alcohol use, blood pressure, and BMI. Demographics and cancer diagnostics were collected for the individuals whom caregivers supported. Linear regression, multivariate analyses, and moderator analyses were performed. RESULTS: Of the 78 caregivers, the mean age was 63.9 (S.D.=13.1); 59% identified as female; 97% identified as White. Regression analyses indicated that caregivers who reported higher levels of trait mindfulness reported significantly less perceived stress (b= -4.38, SE= 0.88, p <.001), lower levels of depression (b= -3.74, SE= 1.10, p = .001), greater caregiver quality of life (b= -9.05, SE=2.12, p < .001), better sleep quality (b= -0.98, SE=0.44, p = 0.03), and lower rates of tobacco use (b= -10.12, SE= 3.43, p =.003). Trait mindfulness was not significantly related to diet, alcohol use, blood pressure, or BMI. CONCLUSIONS: Higher levels of trait mindfulness are associated with positive mental and physical health measure for caregivers. Future research would benefit from further examining mindfulness-based interventions and their impacts in mitigating the negative toll of caregiving in the context of cancer.

Use of the ICRP system for the protection of marine ecosystems.

The International Commission on Radiological Protection (ICRP) recently reinforced the international system of radiological protection, initially focused on humans, by identifying principles of environmental protection and proposing a framework for assessing impacts of ionising radiation on non-human species, based on a reference flora and fauna approach. For this purpose, ICRP developed dosimetric models for a set of Reference Animals and Plants, which are representative of flora and fauna in different environments (terrestrial, freshwater, marine), and produced criteria based on information on radiation effects, with the aim of evaluating the level of potential or actual radiological impacts, and as an input for decision making. The approach developed by ICRP for flora and fauna is consistent with the approach used to protect humans. The International Atomic Energy Agency (IAEA) includes considerations on the protection of the environment in its safety standards, and is currently developing guidelines to assess radiological impacts based on the aforementioned ICRP approach. This paper presents the method developed by IAEA, in a series of meetings with international experts, to enable assessment of the radiological impact to the marine environment in connection with the Convention on the Prevention of Marine Pollution by Dumping of Wastes and Other Matter 1972 (London Convention 1972). This method is based on IAEA's safety standards and ICRP's recommendations, and was presented in 2013 for consideration by representatives of the contracting parties of the London Convention 1972; it was approved for inclusion in its procedures, and is in the process of being incorporated into guidelines.

Advances in NORM management in Norway and the application of ICRP's 2007 recommendations.

In Norway, the largest reported quantities of radioactive discharges and radioactive waste containing naturally occurring radioactive material (NORM) come from the oil and gas sector, and smaller quantities of other NORM waste are also produced by industrial or mining processes. The Gulen final repository for radioactive waste from the oil and gas industry from the Norwegian continental shelf was opened in 2008 and has a capacity of 6000 tonnes. As of 1 January 2011, a new regulation was enforced whereby radioactive waste and radioactive pollution was integrated in the Pollution Control Act from 1981. This means that radioactive waste and radioactive pollution are now regulated under the same legal framework as all other pollutants and hazardous wastes. The regulation establishes two sets of criteria defining radioactive waste: a lower value for when waste is considered to be radioactive waste, and a higher value, in most cases, for when this waste must be disposed of in a final waste repository. For example, waste containing ≥ 1 Bq/g of Ra-226 is defined as radioactive waste, while radioactive waste containing ≥ 10 Bq/g of Ra-226 must be disposed of in a final repository. Radioactive waste between 1 and 10B q/g can be handled and disposed of by waste companies who have a licence for handling hazardous waste according to the Pollution Control Act. Alternatively, they will need a separate licence for handling radioactive waste from the Norwegian Radiation Protection Authority. The goal of the new regulation is that all radioactive waste should be handled and stored in a safe manner, and discharges should be controlled through a licensing regime in order to avoid/not pose unnecessary risk to humans or the environment. This paper will elaborate on the new regulation of radioactive waste and the principles of NORM management in Norway in view of the International Commission on Radiological Protection's 2007 Recommendations.

Mice lacking the Raf-1 kinase inhibitor protein exhibit exaggerated hypoxia-induced pulmonary hypertension.

BACKGROUND AND PURPOSE: Increased pulmonary vascular remodelling, pulmonary arterial pressure and pulmonary vascular resistance characterize the development of pulmonary arterial hypertension (PAH). Activation of the Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)1/2 is thought to play an important role in PAH and Raf-1 kinase inhibitor protein (RKIP), negatively regulates this pathway. This study investigated whether genetic deletion of RKIP (and hence ERK1/2 up-regulation) resulted in a pulmonary hypertensive phenotype in mice and investigated a role for RKIP in mitogen-regulated proliferative responses in lung fibroblasts. EXPERIMENTAL APPROACH: Pulmonary vascular haemodynamics and remodelling were assessed in mice genetically deficient in RKIP (RKIP-/-) after 2 weeks of either normoxia or hypoxia. Immunoblotting and immunohistochemistry were used to examine phosphorylation of Raf-1, RKIP and ERK1/2 in mouse pulmonary arteries. In vitro, RKIP inhibition of mitogen signalling was analysed in CCL39 hamster lung fibroblasts. KEY RESULTS: RKIP-/- mice demonstrated elevated indices of PAH and ERK1/2 phosphorylation compared with wild-type (WT) mice. Hypoxic RKIP-/- mice exhibited exaggerated PAH indices. Hypoxia increased phosphorylation of Raf-1, RKIP and ERK1/2 in WT mouse pulmonary arteries and Raf-1 phosphorylation in RKIP-/- mouse pulmonary arteries. In CCL39 cells, inhibition of RKIP potentiated mitogen-induced proliferation and phosphorylation of RKIP, and Raf-1. CONCLUSIONS AND IMPLICATIONS: The lack of RKIP protein resulted in a pulmonary hypertensive phenotype, exaggerated in hypoxia. Hypoxia induced phosphorylation of RKIP signalling elements in WT pulmonary arteries. RKIP inhibition potentiated mitogen-induced proliferation in lung fibroblasts. These results provide evidence for the involvement of RKIP in suppressing the development of hypoxia-induced PAH in mice.

Endothelial ET(B) limits vascular remodelling and development of pulmonary hypertension during hypoxia.

BACKGROUND: We hypothesised that the potential protective effects of endothelial ET(B) are important in limiting pulmonary vascular muscularisation, vasoconstriction and the development of pulmonary arterial hypertension in response to hypoxia. METHODS: EC-specific ET(B) knockout mice (EC ET(B)(-/-)) and control mice (ET(B)(f/f)) were subjected to hypobaric hypoxic (10% FiO2) or normoxic conditions for 14 days before assessment of right ventricular pressure and pulmonary vascular morphology and function. RESULTS: During normoxia, no difference in right ventricular pressure was detected between EC ET(B)(-/-) (23.7 +/- 1.7 mm Hg) and ET(B)(f/f) mice (20.2 +/- 1.5 mm Hg). Hypoxia induced an exaggerated increase in right ventricular pressure in EC ET(B)(-/-) mice (34.4 +/- 1.2 mm Hg vs. 24.6 +/- 1.4 mm Hg), accompanied by an increase in right ventricular mass. No effect was observed in ET(B)(f/f) mice. Endothelin-1 constricted pulmonary arteries from both groups, although maximum response was similar irrespective of inspired oxygen or genotype. Hypoxia increased the percentage of muscularised vessels in both groups of mice, but the percentage increase was significantly greater in EC ET(B)(-/-) mice. CONCLUSIONS: The potential protective effects of endothelial ET(B) are important in limiting pulmonary vascular muscularisation and the development of pulmonary arterial hypertension in response to hypoxia.

Treatment with the Kv7 potassium channel activator flupirtine is beneficial in two independent mouse models of pulmonary hypertension.

BACKGROUND AND PURPOSE: Voltage-gated potassium (K(v)) channels contribute to resting membrane potential in pulmonary artery smooth muscle cells and are down regulated in patients with pulmonary arterial hypertension (PAH) and a contribution from K(v)7 channels has been recently proposed. We investigated the effect of the K(v)7 channel activator, flupirtine, on PAH in two independent mouse models: PAH induced by hypoxia and spontaneous PAH in mice over-expressing the 5-HT transporter (SERT(+) mice). EXPERIMENTAL APPROACH: Right ventricular pressure was assessed in vivo in mice chronically treated with flupirtine (30 mg.kg(-1).day(-1)). In separate in vitro experiments, pulmonary arteries from untreated mice were mounted in a wire myograph. Relaxations to acute administration of flupirtine and contractions to K(v) channel blocking drugs, including the K(v)7 channel blocker linopirdine, were measured. KEY RESULTS: In wild-type (WT) mice, hypoxia increased right ventricular pressure, pulmonary vascular remodelling and right ventricular hypertrophy. These effects were attenuated by flupirtine, which also attenuated these indices of PAH in SERT(+) mice. In the in vitro experiments, flupirtine induced a potent relaxant response in arteries from untreated WT and SERT(+) mice. The relaxation was fully reversed by linopirdine, which potently contracted mouse pulmonary arteries while other K(v) channel blockers did not. CONCLUSIONS AND IMPLICATIONS: Flupirtine significantly attenuated development of chronic hypoxia-induced PAH in mice and reversed established PAH in SERT(+) mice, apparently via K(v)7 channel activation. These results provide the first direct evidence that drugs activating K(v)7 channels may be of benefit in the treatment of PAH with different aetiologies.

Differential effects of 17beta-estradiol upon stroke damage in stroke prone and normotensive rats.

We previously reported that during pro-estrus (high endogenous estrogen levels), brain damage after middle cerebral artery occlusion (MCAO) was reduced in stroke-prone spontaneously hypertensive rats (SHRSP) but not in normotensive Wistar Kyoto rat (WKY). In the present study, we examined the effect of exogenous estrogen on brain damage after MCAO in SHRSP and WKY. A 17beta-estradiol (0.025 mg or 0.25 mg, 21 day release) or matching placebo pellet was implanted into ovariectomized WKY and SHRSP (3 to 4 months old) who then underwent distal diathermy-induced MCAO 2 weeks later. Plasma 17beta-estradiol levels for placebo and 17beta-estradiol groups were as follows: WKY 0.025 mg 16.4 +/- 8.5 (pg/mL, mean +/- SD) and 25.85 +/- 12.6; WKY 0.25 mg 18.2 +/- 9.0 and 69.8 +/- 27.4; SHRSP 0.25 mg 20.7 +/- 8.8 and 81.0 +/- 16.9. In SHRSP, infarct volumes at 24 hours after MCAO were similar in placebo and 17beta-estradiol groups: SHRSP 0.025 mg 126.7 +/- 15.3 mm (n = 6) and 114.0 +/- 14.1 mm (n = 8) (not significant); SHRSP 0.25 mg 113.5 +/- 22.3 mm (n = 8) and 129.7 +/- 26.2 mm (n = 7) (not significant), respectively. In WKY, 17beta-estradiol significantly increased infarct volume by 65% with 0.025 mg dose [36.1 +/- 20.7 mm (n = 8) and 59.7 +/- 19.3 mm (n = 8) (P = 0.033, unpaired t-test)] and by 96% with 0.25 mg dose [55.9 +/- 36.4 mm (n = 8) and 109.7 +/- 6.7 mm (n = 4) (P = 0.017)]. Thus, 17beta-estradiol increased stroke damage in normotensive rats with no significant effect in stroke-prone rats. Despite being contrary to our hypothesis, our findings add substance to the recently reported negative effects of 17beta-estradiol in clinical studies.

Loss of expression of MLH1, MSH2, MSH6, and PTEN related to endometrial cancer in 68 patients with endometrial hyperplasia.

Derangements in the tumor suppressor gene PTEN and the mismatch-repair genes, hMLH1, hMSH2, and hMSH6, have an important role in endometrial carcinogenesis. The purpose of this study was to assess immunohistochemically the pattern of protein expression for these genes in 68 patients with endometrial hyperplasia and to determine the relation of protein expression to cancer development or coexistence of cancers. Loss of expression of these genes also was evaluated as potential tumor markers for clinical use. PTEN and hMLH1 both showed loss of expression in 55% of specimens from 18 patients with subsequent or coexisting carcinoma. D&C specimens from 50 patients who did not develop cancer (10 patients underwent hysterectomy within 2 years; 40 had no hysterectomy; follow-up of 10-20 years), expressed protein at a much higher frequency (92% for PTEN and 98% for hMLH1). The parameter with the strongest independent relation to subsequent or coexisting carcinoma in a stepwise multiple logistic regression analysis was hMLH1. Evaluation of the investigated factors as prognostic markers for tumor development showed high specificity (92% for PTEN, 98% for MLH1) at the expense of sensitivity (56% for PTEN, 56% for MLH1). The results were compared with the results of the computerized image analysis algorithm, the D-score.

4-Hydroxynonenal immunoreactivity is increased in human hippocampus after global ischemia.

Oxidative stress and lipid peroxidation may contribute to the pathology of neurodegenerative disorders such as Alzheimer's disease (AD) and cerebral ischemia. 4-Hydroxynonenal (4-HNE) is a toxic by-product of lipid peroxidation, and immunoreactivity to 4-HNE has been used to examine lipid peroxidation in the pathogenesis of AD and ischemia. This study sought to determine 1) if there are cellular alterations in 4-HNE immunoreactivity in the human hippocampus after global ischemia, and 2) whether possession of an apolipoprotein E (APOE) epsilon4 allele influenced the extent of 4-HNE immunoreactivity. 4-HNE immunoreactivity was assessed semi-quantitatively in the temporal lobe of a group of controls (n = 44) and in a group of patients who had an episode of global ischemia as a result of a cardiorespiratory arrest and subsequently died (n = 56, survival ranged from 1hr to 42 days). There was minimal cellular 4-HNE immunoreactivity in the control group. However, compared to controls, 4-HNE immunoreactivity was significantly increased in neurons (p < 0.0002) and glia (p < 0.0001) in the hippocampal formation after global ischemia. Possession of an APOE epsilon4 allele did not influence the extent of neuronal or glial 4-HNE immunostaining in the control or global ischemia group. There was a significant negative correlation between the extent of neuronal 4-HNE immunoreactivity with survival period after global ischemia (r2 = 0.0801; p < 0.036) and a significant positive correlation between the extent of glial 4-HNE immunoreactivity and survival after global ischemia (r2 = 0.2958; p < 0.0001). The data indicate a marked increase in neuronal and glial 4-HNE. This substantiates a role for lipid peroxidation in the pathogenesis of cerebral ischemia. There was no indication that APOE genotype influenced the extent of 4-HNE immunoreactivity.

Recovery of autonomic nervous activity after myocardial infarction demonstrated by short-term measurements of SDNN.

OBJECTIVE: Heart rate variability (HRV) has been demonstrated to be a risk factor after acute myocardial infarction (AMI). In the present study serial measurement of SDNN (standard deviation of the mean of qualified NN-interval) in short intervals was used to assess HRV changes after AMI, and determine the role of these as independent risk factors compared to clinical, arrhythmic, ischemic and anamnestic variables. Measurements from a normal healthy middle-aged male population were used as reference (n = 63). METHODS: SDNN from a five-minute period during day and night-time, respectively, was examined in 103 patients 1 week (n = 54), 1 month (n = 72) and 12-16 months (n = 54) after infarction. RESULTS: Day SDNN did not change during one-and-a-half years after AMI, and was significantly reduced compared with healthy males. Night SDNN, low after 1 week, with recovery 1 month after AMI, was significantly reduced compared with healthy males early, but not late after AMI. Thus, the study indicated during day-time a continuous abnormal sympathetic preponderance in the course of 16 months after AMI, and during night-time a gradual recovery of parasympathetic preponderance beginning early after AMI. CONCLUSION: One week after AMI day-time SDNN of <30 ms, and night-time SDNN of < 18 ms, age > or =60 years, and myocardial ischemia (Holter monitoring) were independent predictors of 9 years' mortality. One and 12-16 months after AMI reduced day and night-time SDNN had no prognostic implication.

Increased neuronal damage and apoE immunoreactivity in human apolipoprotein E, E4 isoform-specific, transgenic mice after global cerebral ischaemia.

Apolipoprotein E (apoE, protein; APOE, gene) is expressed as three isoforms in humans (E2, E3, E4). The APOE-epsilon4 allele is associated with a poor outcome in patients after head injury of which ischaemic brain damage is a contributor of mortality and morbidity. The aim of the study was to determine whether mice expressing human APOE-epsilon4 displayed more extensive ischaemic neuronal damage 72 h after transient global ischaemia compared with mice which express human APOE-epsilon3. APOE-epsilon3 and -epsilon4 transgenic mice, under the control of a human promoter, were used which express human APOE in neurons and glia. Ischaemic neuronal damage in the CA1 pyramidal cell layer in the APOE-epsilon4 transgenic mice was significantly greater than in the APOE-epsilon3 mice after global ischaemia (36.4+/-8.9%, 18.2+/-7.3%; P<0.05). This was associated with more extensive neuronal apoE immunoreactivity in the CA1 pyramidal cell layer in the APOE-epsilon4 transgenic mice compared with APOE-epsilon3 transgenic mice. In contrast, in the caudate nucleus, there were similar levels of ischaemic neuronal damage in the APOE-epsilon3 and -epsilon4 transgenic mice (39.2 +/-10.1%; 44.6+/-8.4%, P = 0.32). In the caudate, similar numbers of neurons were immunostained for apoE in the APOE-epsilon3 and -epsilon4 transgenic mice. The present study demonstrated that the APOE-epsilon4 allele is associated with an increased vulnerability of a specific brain region to the effects of global ischaemia, which is closely associated with an increase in neuronal apoE. The data extend previous work and are consistent with an association of the APOE-epsilon4 allele with a poor outcome after acute brain injury in humans.

Intraventricular infusion of apolipoprotein E ameliorates acute neuronal damage after global cerebral ischemia in mice.

The ability of intraventricular infusion of apolipoprotein E (apoE) to reduce neuronal damage after global cerebral ischemia was investigated in apoE-deficient and wild-type mice. ApoE (5 microg/mL lipid-conjugated derived from human plasma; 1 microL/h, continuous infusion) significantly reduced neuronal damage in the caudate nucleus and CA2 pyramidal cell layer by approximately 50% in apoE-deficient mice after global ischemia compared to vehicle infusion. In wild-type mice infused with apoE, there was a trend for ischemic neuronal damage to be reduced. ApoE-infused mice had a marked reduction in 4-hydroxynonenal immunoreactivity, as a marker of lipid peroxidation. The results show that the presence of apoE at or after the time of injury can be neuroprotective, possibly via an anti-oxidant mechanism.

Specificity studies of an antibody developed against a mucin-type glycoprotein.

The specificity of a new anti-epiglycanin antibody (AE-3) which recognizes a mucin-type glycoprotein, the Human Carcinoma Antigen, found in the blood of patients with carcinomas, was studied. Information regarding the chemical nature of the antibody binding site was obtained by altering the structure of epiglycanin by chemical or enzymic means and testing the product in a competitive binding assay for inhibition of the binding of AE-3 to epiglycanin. The need for a high molecular weight antigen containing clustered T disaccharide, Gal,1-3GalNAc, was demonstrated. The specificity was further explored by inhibition studies with glycopeptides having one to three mono- to disaccharides. The results were interpreted using computer graphics molecular modeling which predicted the specific recognition of hydroxyl groups on oligosaccharides on adjacent amino acids. Thus T antigen O-linked glycopeptide tumour markers can be designed to be distinguished by antibodies by the amount of clustering of their oligosaccharides.

DNA polymorphisms of the apolipoprotein B gene (XbaI, EcoRI, and MspI RFLPs) in Norwegians at risk of atherosclerosis and healthy controls.

OBJECTIVES: Apo B is the exclusive protein constituent of LDL and is ligand on LDL, recognized and bound by the LDL receptor. Several restriction fragment length polymorphisms (RFLPs) of the apo B gene have been shown to be associated with variation in serum lipid levels in different populations. In this study we sought to determine the frequency of XbaI, EcoRI, and MspI polymorphisms and the haplotypes generated by these three polymorphic sites of the apo B gene and their influence on lipid levels in a sample of Norwegian subjects at risk of atherosclerosis and healthy control subjects. METHODS AND RESULTS: 108 White Norwegians at risk of atherosclerosis (cases) and 64 healthy individuals (controls) were examined for possible association between the alleles at the XbaI (X), EcoRI (R), and MspI (M) polymorphic restriction sites of the apolipoprotein B gene and serum lipid levels. The frequency of the M allele (absence of restriction site) was significantly higher in cases with high total cholesterol (TC), high low-density lipoprotein cholesterol (LDLC), and high apolipoprotein B (apo B) than in controls with normal TC, LDLC, and apo B (P < 0.04, P < 0.02, and P < 0.01, respectively). The frequencies of apo B genotypes detected with XbaI, EcoRI, and MspI did not differ significantly between cases and control subjects. A significant association between MspI genotypes and TC (P < 0.02), LDLC (P = 0.03), and apo B (P = 0.001) was observed only in cases. However, cases with the genotype M+/M+ had the lowest and those with the genotype M+/M- had the highest levels of serum TC, LDLC, and apo B. We did not observe any significant association between the alleles or genotypes detected with XbaI or EcoRI and serum lipid levels. In cases, genotypes defined by EcoRI and MspI RFLP paired loci differed significantly for apo B (chi 2 = 19; P = 0.007) but not for other blood lipids. EcoRI and MspI RFLPs change glutamic acid (Glu) 4154 to lysine (Lys) and arginine (Arg) 3611 to glutamine (Gln), respectively, which lie near the low density lipoprotein receptor binding region of apo B. Haplotypes containing "Lys/Arg Lys/Arg" (all basic amino acids) in cases were associated with low serum TC, LDLC, and apo B. In individuals at risk of atherosclerosis the concentration of serum lipids tends to be inversely related to the number of lysine and arginine. CONCLUSION: We conclude that variations in the apo B gene, resulting in changes of charged amino acids, affect the circulating blood lipids and that these may contribute to the risk of atherosclerosis.

Transient Tat activation of the HIVLAV/Lai-1 LTR by primary HIV-1 phenotypic variants in HeLaT4LTRbeta-gal cells.

The rapid/high and slow/low phenotypic variants of primary HIV-1 isolates can be distinguished by their differential co-receptor utilization and their ability to productively infect established cell lines. To reveal possible differences in Tat-mediated transactivation, the potential for primary isolate Tat proteins to transactivate the LTR from the laboratory strain HIVLAV/Lai-1 was examined. Using either cell-mediated or PEG-induced fusion of cells infected with primary HIV-1 isolates and HeLaT4LTRbeta-gal cells, it was clear that the Tat protein encoded by all patient isolates efficiently activated transcription from the HIVLAV/Lai-1 LTR. However, infection of HeLaT4LTRbeta-gal cells by primary HIV-1 isolates was transient, suggesting the development of a postpenetration host control of HIV-1 replication at the level of tat activation, a feature not observed for the laboratory-adapted strain HIVIIIB. Although plasmid vectors based on the HIVLAV/Lai-1 LTR remain useful for the development of susceptible established cell lines for titrating primary HIV-1 isolates, the efficacy of such a system would depend upon the stability/duration of Tat activation.

ST-segment deviation during 24-hour ambulatory electrocardiographic monitoring and exercise stress test in healthy male subjects 51 to 75 years of age: the Copenhagen City Heart Study.

BACKGROUND: Although ST-segment deviation has been evaluated and used during many years both on continuous electrocardiographic Holter monitoring and during exercise stress testing, considerable controversy still remains concerning the prevalence and diagnostic significance of fortuitously discovered ST-segment deviation in asymptomatic healthy persons. METHODS AND RESULTS: The occurrence of ST-segment deviation was studied in a population of 63 clinically healthy male subjects 51 to 75 years of age, with the use of 24-hour Holter monitoring and exercise stress testing. The subjects were recruited from the Copenhagen City Heart Study and were without cardiovascular risk factors, chronic diseases, or medication and without cardiovascular events during 5 to 12 years before and 3 to 5 years after admission. The specificity, that is, the probability of displaying a negative test result in healthy subjects without disease, was 1.0 when using as criterion for significant ST-segment deviation a horizontal or descending ST-segment depression of >0.20 mV or ST-segment elevation >/=0.15 mV during Holter monitoring, and acceptable, for example, 0.95, when using as criterion a horizontal or descending ST-segment depression of >/=0.15 mV during Holter monitoring or at the exercise test, respectively. Furthermore, the specificity was 0.95 when a horizontal or downsloping ST-segment depression of 0.1 mV was displayed in both the Holter and exercise electrocardiographic recording system. CONCLUSIONS: Thus in asymptomatic persons, the usual criterion for significant ST-segment depression of 0.1 mV can be applied when occurring in both electrocardiographic recording systems. However, if one test alone is used, the criterion of significant ST-segment depression should be 0.15 mV. Absence of ST-segment deviation during Holter monitoring and exercise stress testing, indicated with a specificity of 1.0 or 0.95 according to choice of criterion, implies that the person is in a healthy state.

Prognostic implications of ventricular ectopy one week, one month, and sixteen months after an acute myocardial infarction. Danish Study Group on Verapamil in Myocardial Infarction.

BACKGROUND: Ventricular ectopy early after an acute myocardial infarction (AMI) has previously been demonstrated to predict mortality. Less information is available about the prognostic implications of ventricular ectopy occurring late after an AMI, and no information is available about the prognostic implication of the development of ventricular ectopy during the first year after an AMI. HYPOTHESIS: The purpose of the present prospectively conducted trial, a part of the Danish Verapamil Infarction Trial II (DAVIT II), was to evaluate the prognostic implication of (1) ventricular premature complexes (VPCs) recorded by 24-h Holter monitoring 1 week, 1 month, and 16 months after an AMI; and (2) development of > 10 VPCs/h or of any complex ventricular ectopy, that is, pairs, more than two types of VPCs, ventricular tachycardia, or > 10 VPCs/h during follow-up after an AMI. METHODS: Patients were monitored 1 week (n = 250), 1 month (n = 210), and 16 months (n = 201) after AMI. RESULTS: Multivariate analyses based on history, clinical findings, and ventricular ectopy showed the following results: After 1 week, > 10 VPCs/h (p = 0.0006) and heart failure (p < 0.007); after 1 month, > 10 VPCs/h (p = 0.003) and resting heart rate (p < 0.02); and after 16 months, ventricular tachycardia (p = 0.002) independently predicted long-term mortality. Mortality was significantly predicted by the development of > 10 VPCs/h from 1 week to 1 month (p = 0.003) and 16 months (p = 0.03), and from 1 to 16 months (p = 0.007) after AMI, as well as by the development of any complex ventricular ectopy from 1 week to 1 month (p = 0.02) and 16 months (p = 0.01), and from 1 to 16 months (p = 0.04) after AMI. CONCLUSION: The present study demonstrated that 1 week and 1 month after an AMI the quantity of VPCs, that is, > 10 VPCs/h, predicted mortality, whereas 16 months after an AMI the quality of VPCs, that is, ventricular tachycardia, predicted mortality.

Effect of verapamil on heart rate variability after an acute myocardial infarction. Danish Verapamil Infarction Trial II.

Because decreased heart rate variability measured after an acute myocardial infarction (AMI) has been demonstrated to predict subsequent mortality and sudden death, and an efficacy analysis of the Danish Verapamil Infarction Trial II (DAVIT II) demonstrated that long-term postinfarction treatment with verapamil significantly reduced sudden death, the aim of the present substudy was to evaluate the effect of verapamil on heart-rate variability in the time and frequency domain, measured in two 5-minute segments during the day and night. Thirty-eight patients were examined by Holter monitoring, at 1 week, that is, before randomization, and at 1 month after infarction; 22 of the patients were examined 12-16 months after infarction as well. In both treatment groups (verapamil and placebo) no significant alteration of heart rate variability during the day-time was demonstrated from before to after 1 and 12-16 months of treatment. In accord with the known reduction of overall heart rate by verapamil, a significant increase of mean NN interval from before to after 1 (P = 0.0004) and 12-16 months (P = 0.004) of treatment was seen in the verapamil, but not in the placebo, group at night. Parameters generally interpreted as an index of parasympathetic modulation, that is, RMSSD, pNN50, and high-frequency power, increased significantly at 1 month (P = 0.04, P = 0.03, NS, respectively) and 12-16 months (P = 0.03, P = 0.04, P < 0.05) after AMI in the verapamil, but not in the placebo, group. In conclusion, the present study indicates that verapamil shifts the autonomic balance to a vagal preponderance or sympathetic attenuation in the postinfarction period.

Marked alterations in the cellular localisation and levels of apolipoprotein E following acute subdural haematoma in rat.

Apolipoprotein E (apoE) plays a role in the response to acute brain injury, the mechanisms as yet remain unknown. In the present study, alterations in the immunohistochemical localisation of apoE in rat cortex were examined at 30 min, 2 h or 4 h following production of an acute subdural haematoma. Levels of apoE were determined in cortex by immunoblotting at 30 min and 4 h post-haematoma. Extensive areas of ischaemic cell damage were observed in the cortex underlying the haematoma with minimal damage observed in shams. In sham animals, apoE immunoreactivity was confined to astrocytes and their processes. Following the haematoma induction, apoE immunoreactivity was dramatically altered. At 30 min post-haematoma, intense apoE staining was observed in clusters of neuronal perikarya and the neuropil throughout the cortical layers underlying the haematoma and this persisted at 2 h and 4 h post-haematoma. Additionally, at 4 h post-haematoma marked apoE staining of discrete foci within the neuropil closely associated with capillaries was consistently observed in the ipsilateral cortex. Immunoblotting indicated there were no significant alterations in the cortical levels of apoE at 30 min post-haematoma but, at 4 h post-haematoma, there was a significant elevation (27%, P < 0.001) in the levels of apoE in cortex underlying the haematoma compared to control levels. The results indicate that following acute subdural haematoma, a rapid cellular redistribution of apoE occurs and precedes a significant elevation in the levels of apoE. These alterations in apoE may occur, at least initially, as part of the brain's protective response to injury.