Diagnostic accuracy of computer aided electrocardiogram analysis in dogs.

OBJECTIVES: Evaluation of a computerised electrocardiogram algorithm compared to the interpretation of a team of board-certified veterinary cardiologists. MATERIALS AND METHODS: This was a cross-sectional retrospective cohort study. A total of 399 electronic canine electrocardiogram recordings screened from 1391 electrocardiograms were enrolled in the study. A panel of seven cardiologists, masked to patient information, evaluated electrocardiograms for the following: P-wave amplitude and duration; PR-interval; R-wave amplitude; QRS duration; heart rate; mean electrical axis; and final overall diagnosis for the detection of arrhythmia and any abnormal electrocardiogram anomaly. RESULTS: The sensitivity of the electrocardiogram algorithm for detecting arrhythmias was 99.7% (95% confidence intervals, CI: 98.5 to 99.9) and the specificity was 99.5% (95% CI: 98.0 to 99.9) compared to the consensus result created by panel of cardiologists. The sensitivity of the algorithm for the detection of any electrocardiogram anomaly, including abnormal measurements, was 71.3% (95% CI: 65.5 to 76.7) and the specificity was 35.1% (95% CI: 27.0 to 43.8) compared to the panel of cardiologists. CLINICAL SIGNIFICANCE: The electrocardiogram algorithm was shown to have high sensitivity for the detection of arrhythmias, but not all electrocardiogram anomalies. The results support the use of this algorithm as a tool to aid in the triage of the electrocardiogram workflow.

Transvenous pacing implantation: techniques, tips, and lessons learned along the way.

The right ventricular apex has been the traditional site for lead placement in veterinary patients who require permanent cardiac pacing therapy for atrioventricular block and sick sinus syndrome. Implantation of leads in this location is a straightforward procedure that most veterinary cardiologists perform routinely. Pacing at the right ventricular apex, however, has been demonstrated to have long-term deleterious effects on the left ventricular function in numerous patient populations and animal models. Alternative lead placement sites and pacing system configurations have been developed, and the purpose of this review article is not to review the literature or the decision-making process in selecting a specific pacing system but rather to share the experiences of our group with the use of alternative pacing implantation techniques for veterinary patients in need of permanent cardiac pacing.

Cost-effectiveness of bazedoxifene incorporating the FRAX® algorithm in a European perspective.

UNLABELLED: The cost-effectiveness of bazedoxifene was compared to placebo in France, Germany, Italy, Spain, Sweden and the UK from a healthcare perspective using FRAX® for both fracture risks and for treatment efficacy. Cost/QALY differences were explained to a large extent by differences in fracture risk. INTRODUCTION: In cost-effectiveness modelling of osteoporosis treatments, the fracture risk has traditionally been calculated with risk adjustments based on age, bone mineral density and prior fracture. However, knowledge of additional clinical risk factors contributes to fracture risk assessment as demonstrated by the FRAX® tool. Bazedoxifene, a new selective estrogen receptor modulator for the treatment and prevention of osteoporosis, has been shown in a phase III clinical trial to reduce the risk of osteoporotic fractures in women. In an analysis using FRAX®, the efficacy of bazedoxifene was greater in patients with higher fracture risk. METHODS: The aim of this study was to evaluate the cost-effectiveness of bazedoxifene compared to placebo in France, Germany, Italy, Spain, Sweden and the UK from a healthcare perspective using FRAX®. A Markov cohort model was adapted to incorporate the FRAX® risk factors. FRAX® produces relative risks for hip fractures and major osteoporotic fractures. Patients were given a 5-year intervention, reducing the risk of fractures in a risk-dependent manner. The effect of treatment on fractures was assumed to decline linearly over 5 years after the intervention. RESULTS: There are large cost/quality-adjusted life year variations between countries in the European setting studied. The base case values ranged from cost saving (Sweden) to EUR 105,450 (Spain) in 70-year-old women with a T-score of -2.5 SD and a prior fracture. CONCLUSION: Bazedoxifene can be a cost-effective treatment for postmenopausal osteoporosis. The variability between countries was explained to a large extent by differences in fracture risk, and the estimated cost-effectiveness was highly dependent on the population's FRAX®-estimated probability of major osteoporotic fracture.

FRAX and its applications in health economics--cost-effectiveness and intervention thresholds using bazedoxifene in a Swedish setting as an example.

BACKGROUND: An important aspect of cost-effectiveness analysis of osteoporosis is to accurately model the fracture risk and mortality related to the patient groups in the analysis. The estimation of fracture risk is based on a number of factors, such as the level of general risk of the normal population, the effect of treatment and the prevalence of clinical risk factors (CRFs) for fracture. Fracture risk has traditionally been calculated with risk adjustments based on age, bone mineral density and prior vertebral fracture. The treatment effect has been derived from clinical trials and, in the absence of subgroup analyses, the same efficacy has been assumed irrespective of the fracture risk of the population. The FRAX tool enables the estimation of risk based on a wider range of risk factors, and treatment efficacy that is dependent on the level of risk in the analyzed population. The objective was to describe the implementation of the FRAX algorithms into health economic osteoporosis models and to highlight how it differs from traditional risk assessment. METHODS: The selective estrogen receptor modulator, bazedoxifene, was evaluated in a Swedish setting with traditional and FRAX-based risk assessment in a previously developed Markov model that included fractures and thromboembolic events, and also was adapted to accommodate risk-dependent efficacy, which is available for bazedoxifene. RESULTS: The traditional approach gave lower ICERs at ages up to 60 years compared to the FRAX method when only considering age, BMD and prior fracture. At 70 years and older and when adding more CRFs with the FRAX approach, the FRAX ICER decreased and fell below the traditional approach. The risk dependant efficacy was the main reason for lower ICERs with FRAX in women at higher risk of fracture. DISCUSSION: FRAX applied in cost-effectiveness analyses is a more granular method for the estimation of fracture risk, mortality and efficacy compared to previous approaches that can also improve case finding. Furthermore, it facilitates the estimation of cost-effectiveness for various types of patients with different combinations of CRFs, which more closely matches patients in clinical practice.

Optical and confocal microscopy observations of screw dislocations in smectic-A liquid crystals.

We present experimental evidence of the presence of isolated screw dislocations in smectic-A liquid crystals observed by polarizing microscopy. In a wedge-shaped homeotropic cell, the edge and screw dislocations interaction gives rise to a strong-enough optical contrast and makes visible their mutual intersections at temperatures close to the smectic-A to smectic-C phase transition temperature. The nature of the defects is confirmed by confocal microscopy observations. At large scale we observe a forest of screw dislocations, perpendicular to the smectic layers, across the thickness of the cell (end-on configuration). Their density varies between 10(9) and 10(12) m-2. In situ observations of dislocations under stress, in the optical microscope, provide quantitative information about the screw-edge dislocation interactions. The latter interaction is calculated in the unharmonic approximation and it gives rise to an observed yield stress.

Liquid crystal helical ribbons as isometric textures.

Deformations that conserve the parallelism and the distances--between layers, in smectic phases; between columns, in columnar phases--are commonplace in liquid crystals. The resulting isometric deformed textures display specific geometric features. The corresponding order parameter singularities extend over rather large, macroscopic, distances, e.g., cofocal conics in smectics. This well-known picture is modified when, superimposed to the 1D or 2D periodicities, the structure is helical. However isometry can be preserved. This paper discusses the case of a medium whose structure is made of 1D modulated layers (a lamello-columnar phase), assuming that the modulations rotate helically from one layer to the next. The price to pay is that any isometric texture is necessarily frustrated; it consists of layers folded into a set of parallel helicoids, in the manner of a screw dislocation (of macroscopic Burgers vector), the modulations being along the helices, i.e. double-twisted. The singularity set is made of two helical disclination lines. We complete this geometric analysis by a crude calculation of the energy of a helical ribbon. It is suggested that the helical ribbons observed in the B7 phase of banana-like molecules are such isometric textures. As a side result, let us mention that the description of double-twist, traditionally made in terms of a partition of the director field into nested cylinders, could more than often be profitably tested against a partition into nested helicoids.

Textural analysis of a mesophase with banana shaped molecules.

Observed under the polarizing microscope, the B7bis phase in the banana compound D14F3 [J.P. Bedel et al., Liq. Cryst. 27, 1411 (2000)] displays two types of textures of defects, namely (a): helical ribbons, that nucleate in large quantities when the samples are quenched from a sufficiently high temperature in the isotropic phase (b)- shapes with no helicity having the structure of developable domains much akin to those observed in columnar phases, either resulting from the annealing of the helical ribbons or nucleating under slow cooling processes. The existence of these two kinds of defects points toward the complex nature of the structure of the B7 phase, which is at the same time a columnar and a smectic phase. Our observations fit the model [M. Kleman, J. Phys. France 46, 1193 (1985)] according to which the geometry of a helical ribbon is that one of the central region of a screw dislocation with a giant Burgers vector, split into two helical disclination lines of strength k = 1/2 which bound the ribbon. Textures and defects, already partly documented, and growth features and annealing processes, not yet reported in the literature, are analyzed. We conclude that the helical ribbons and the developable domains with no helicity are textures of two different B7 states, namely a metastable state and the ground state respectively. Comparative textural analysis is performed for two other banana compounds exhibiting B2 phases.

Defects in a TGBA phase: a theoretical approach.

Following our experimental observations of disclination lines in freely suspended droplets and free-standing films (Yu.A. Nastishin et al., Eur. Phys. J. E 5 353 (2001)), topological defects of the twist grain boundary (TGBA) phase are considered according to two aspects: topological and energetical. There are two classes of line defects, disclinations (as in the cholesteric (N*) phase and the liquid vortices phase (NL*), relating to the directors tripod symmetries) and dispirations (relating to the translation-rotation symmetries); there are no topological point defects. Differences between N*, NL* and TGBA disclinations are physical, not topological. The absence of focal conic domains in the TGBA phase is an immediate consequence of the materialization of the helical axis (along the chi-director); the same feature, coupled to the trend to parallelism of the smectic layers, accounts for the predominance of lambda-lines. Finally, the presence of defects akin to developable domains is explained in the frame of the least curvature model, that requires the introduction of a third type of defects: the densities of edge dislocations of the smectic layers.

Tiling the plane with noncongruent toric focal conic domains

This paper deals with regular arrays of macroscopic defects (focal conic domains) observed when a slab of lamellar phase is sandwiched between two substrates imposing different orientational anchorings. We report, in particular, detailed observations of the texture of a lyotropic lamellar phase in contact with a glass substrate and a lyotropic sponge phase. We consider several models for the defects depending on the material and the substrate parameters. Their energy has a common form, and the main features of the textures are explained in the framework of a simple model where disks of different sizes tile a plane in order to minimize a particular interface energy.

Curvature energy of a focal conic domain with arbitrary eccentricity

The most frequently observed focal conic domains (FCD's) in lamellar phases are those based on confocal paris of ellipse and hyperbola. Experimentally, the eccentricity of the ellipse takes a broad range of values 01 (under the constraint of a fixed major semiaxis of the ellipse); exceptions include situations with large saddle-splay elastic constant and small domains where the applicability of the elastic theory is limited. In realistic cases, a value of eccentricity smaller than 1 is stabilized by factors other than the curvature energy: by dislocations emerging from the FCD's with e not equal0, compression of layers and surface anchoring.

Interactions of procarcinogenic heterocyclic amines and indolocarbazoles with the dioxin receptor.

Cooking of protein-rich food generates procarcinogenic heterocyclic aromatic amines (HCA) in amounts that range in the part per billion levels. HCA have been reported to induce xenobiotic metabolizing enzymes of the cytochrome P450 1A (CYP1A) subfamily, most notably the CYP1A2 isoform. The regulator mechanism of the CYP1A induction by HCA is, however, unclear. Studies in vivo in rats and in primary hepatocyte cultures revealed "that MelQx induced both CYP1A1/1A2 proteins and the corresponding catalytic activities. In contrast to previous studies, no preferential induction of CYP1A2 was observed in the present study. CYP1A1 and CYP1A2 are target genes of the intracellular dioxin receptor. This receptor interacts with xenobiotic response elements (XREs) of target promoters upon binding the environmental pollutant dioxin or related compounds. HCA exhibited capacity to activate the dioxin receptor to a form which interacts with XRE in vitro. Taken together, these results suggest that MelQx regulates both CYP1A isozymes by the same mechanism involving the dioxin receptor. Another group of putative dioxin receptor ligands of dietary orgin are the indolocarbazoles, which are produced in vivo from precursor molecules in cruciferous plants. Indolocarbazoles potently regulated gene expression of a reporter gene driven by a minimal XRE in both mouse and human hepatoma cells. The indolocarbazole-induced human receptor appeared to form more stable complexes with XRE in vitro relative to those generated by the dioxin-activated receptor. This study indicates that the HCA and the indolocarbazoles both represent distinct classes of dietary dioxin receptor agonists.

Induction of cytochrome P4501A isozymes by heterocyclic amines and other food-derived compounds.

The cytochrome P-4501A1 and P-4501A2 enzymes are involved in the metabolic activation of a number of environmental precarcinogens including the food-derived heterocyclic amines. These compounds also induce CYP1A activity in rats, a feature they have in common with several of the xenobiotics (most notably benzo[a]pyrene) which are metabolically activated by the cytochrome P-4501A isozymes. Using an in vitro DNA binding assay and an in vivo functional (transactivating) assay, we have found that the cytochrome P-4501A1 induction response produced by the heterocyclic amines is mediated by the intracellular dioxin receptor. In the absence of ligand, the receptor is inactive and does not bind DNA. In this report we demonstrate a correlation between activation of DNA binding activity of the receptor by the heterocyclic amines and their ability to induce transcription from a minimal dioxin-response element-driven promoter construct. However, relatively high doses of these compounds are required to produce these effects. Therefore, despite a relatively high dietary intake of heterocyclic amines as compared to other cytochrome P-4501A1-inducing substances, the heterocyclic amines most probably only play a minor role in the induction of this enzyme activity. In contrast to the heterocyclic amines, indolo derivatives found in cruciferous vegetables exhibit high affinity for the dioxin receptor and represent potent activators of the DNA binding activity of the receptor. The indolo derivatives are therefore likely to have a larger impact than the heterocyclic amines on human CYP1A1 activity.

Regulation of human dioxin receptor function by indolocarbazoles, receptor ligands of dietary origin.

The intracellular basic helix-loop-helix (bHLH) dioxin receptor mediates signal transduction by dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin). In analogy to nuclear receptors that are members of the steroid hormone receptor superfamily the dioxin receptor is a ligand-inducible transcriptional regulator that directly binds to response elements within regulated genes. The most commonly studied dioxin receptor ligands are dioxin itself and structurally related environmental contaminants. A physiological ligand has not yet been identified. Interestingly, however, indolo[3,2-b]carbazole, a compound formed from precursors in the diet, has been shown to bind the murine dioxin receptor with high affinity in vitro. In the present study we show that this compound and its methylated derivative 5,11-dimethylindolo[3,2-b]carbazole very potently activated transcription from a dioxin or xenobiotic response element (XRE)-driven reporter gene in both murine and human hepatoma cells. This effect was not observed in mutant, dioxin-resistant hepatoma cells which are either deficient in expression of dioxin receptor or the bHLH receptor partner factor Arnt. In vitro indolocarbazoles induced XRE binding activity by the human dioxin receptor-Arnt complex in a dose-dependent manner. Thus, both dioxin- and indolocarbazole-activated forms of dioxin receptor regulate target gene expression by the same mechanism involving recruitment of the bHLH factor Arnt and recognition of the XRE element. Finally, the indolo[3,2-b]carbazole-activated human dioxin receptor appeared to generate more stable complexes with the XRE target sequence relative to those produced by the dioxin-activated receptor form, indicating interesting mechanistic differences between different classes of dioxin receptor ligands in their abilities to modulate human dioxin receptor function.

The heterocyclic amines IQ and MeIQx show no promotive effect in a short-term in vivo liver carcinogenesis assay.

The food-derived heterocyclic amines 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) and 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx) are carcinogenic in rodents as well as in non-human primates (IQ). Using a short-term liver carcinogenesis model the compounds were found to be only weak initiators. It is also possible that these amines are involved in other phases of the carcinogenesis process. In an attempt to study the promotive effects of IQ and MeIQx, these heterocyclic amines were repeatedly given by gavage, over a period of 10 days, to Wistar rats previously initiated with diethylnitrosamine (DEN) and subjected to a partial hepatectomy. The rats were killed 1 month after DEN administration and their livers examined for glutathione-S-transferase positive (GST-P) foci. The positive control, 2-acetylaminofluorene, significantly increased the development of GST-P foci in the DEN-treated rats compared to the negative control, saline. However, neither the IQ- nor the MeIQx-treated groups differed from the controls and thus these amines do not promote the growth of DEN-initiated GST-P liver foci in this model.

Physiologic responses of coronary care patients to visiting.

The authors examined physiologic changes in myocardial infarction patients during a family visit in the cardiac intensive care unit (CICU) and the relationship of these changes to illness variables, patient preference for visits, and patients' perceptions of the supportiveness of the visit. Forty-eight patients were studied for changes in heart rate, blood pressure, ST segment, and oxygen saturation. Patients who had the greatest physiologic changes were among those who had had more severe infarcts. However, many patients in the severe category did not show such changes. Examination of the reactive group revealed that, in addition to having more severe infarcts, it included a greater percentage of smokers than did the nonreactive group. Visit preferences were relatively low, but as visit preferences increased, so did cardiovascular changes. Supportiveness scores were quite high, and these were positively correlated with cardiovascular changes. Clinical and research implications are discussed.

Attention versus avoidance: attributional search and denial after myocardial infarction.

OBJECTIVE: In this study the focus was on two strategies: denial (an avoidant strategy) and causal thinking (an attention strategy) and their relationships to affect after myocardial infarction. DESIGN: Descriptive, correlational. SETTING: Large rural medical center. SAMPLE: The sample comprised 152 recently hospitalized patients with first-time myocardial infarction. MEASURES: A denial scale, a question about causal thinking, and an affect adjective checklist measuring anxiety, hostility, and depression. RESULTS: Denial had a weak but significant negative correlation with anxiety (r = -0.18, p < 0.05). However, denial was not significantly related to either depression or hostility. Regression analysis indicated that both denial (F = 4.84, p = 0.02) and the interaction of denial with causal search (f = 4.77, p = 0.009) were predictors of affect. The interaction indicated that those with high denial who had not searched for a cause were least anxious. A large number of subjects used both attention and avoidant strategies. CONCLUSIONS: The main effect for denial suggests that avoidance is a more effective strategy for reducing anxiety after myocardial infarction than causal search, an attention strategy. However, the fact that many subjects used both strategies suggests that they are not mutually exclusive in the process of adaptation after a heart attack.

In vitro activation of the dioxin receptor to a DNA-binding form by food-borne heterocyclic amines.

The carcinogenic heterocyclic amines, which are formed upon cooking of protein-rich food, are activated in the body mainly by cytochrome P450 IA1 and IA2. Several of these co-called food mutagens have, by enzymatic and immunoblotting techniques, been shown to be weak inducers of cytochrome P450 IA in the rat. To elucidate whether this induction occurs via the dioxin receptor, the capacity of the heterocyclic amines to activate in vitro the dioxin receptor to a DNA-binding form was determined. The activation of the receptor in Hepa cell cytosol was analyzed with a gel-retardation assay using a [32P]3'-end-labeled synthetic oligonucleotide, corresponding to nucleotides -1026 to -999 of the rat cytochrome P450 IA1 gene (XRE1), as probe. Five out of 14 heterocyclic amines had the ability to induce specific DNA-binding activity in the Hepa cell cytosol in a dose-dependent manner. The concentrations eliciting 50% of the maximal effect (EC50) were found to be between 30 and 135 microM. Thus, in comparison to high-affinity ligands such as benzo[a]pyrene (B[a]P; EC50 11.2 nM), and 2,3,7,8-tetrachloro-1,6-dibenzo-p-dioxin (TCDD; EC50 1.9 nM), the activating capacity of the heterocyclic amines is low. Binding to the dioxin receptor has been shown to be dependent on the three-dimensional size of a molecule in relation to a 6.8 x 13.7 A rectangle. The relatively low EC50 values found for the heterocyclic amines might be explained by the smaller size of these molecules when compared to that of B[a]P and TCDD.