Immunosuppressive effects of clozapine and haloperidol: enhanced production of the interleukin-1 receptor antagonist

In schizophrenic patients, multiple immune abnormalities have been reported, including increased production of proinflammatory cytokines. There is some evidence that antipsychotic drugs may have immunosuppressive effects. The aim of this study was to examine the in-vitro effects of different concentrations of antipsychotic agents on cytokine production by human whole blood. We examined the effects of clozapine and haloperidol, 10(-4), 10(-6) and 10(-8)M, on the unstimulated and stimulated (lipopolysaccharide+phytohemagglutinin) production of interleukin-6 (IL-6), IL-10, interferon-gamma (IFNgamma), and the IL-1 receptor antagonist (IL-1RA). Clozapine, 10(-6) and 10(-8)M, and haloperidol, 10(-4), 10(-6), and 10(-8)M, significantly increased the unstimulated and stimulated production of IL-1RA. Clozapine 10(-6)M significantly increased the stimulated production of IFNgamma. Clozapine 10(-4)M significantly suppressed the unstimulated production of IL-6 and IL-1RA and the stimulated production of IL-6, IL-10, IFNgamma and IL-1RA. The results suggest that both clozapine and haloperidol, at concentrations within the therapeutic range, may exert immunosuppressive effects through an enhanced production of IL-1RA.     

Basic principles of MRA

Two types of MR angiography techniques are used in the radiological practice for neurovascular applications: flow based techniques and ultrafast contrast enhanced acquisitions. Both techniques have their specific advantages and limitations. Whereas flow based techniques can be run on most MR scanners, high quality contrast enhanced studies require a state-of-the-art system with high slew rates and dedicated tools to match bolus passage and MR scanning. In this text, we focus on the physical acquisition principles and we illustrate the different phenomena in clinical examples. Numerous studies have proven the clinical applications for the 2 acquisition strategies. So far, an understanding of the basic physics remains necessary to explain occasional artefacts: MR angiography techniques are not yet fully robust. Further optimizations of the current approaches can be expected as there is still a need to improve image quality.     

Blood cyclosporine level soon after kidney transplantation is a major determinant of rejection: insights from the Mycophenolate Steroid-Sparing Trial

Target organs express antigens directly recognized by antigen-specific T cells, thereby precipitating rejection. When early T-cell activation is inhibited, there is a low risk of rejection. We sought to determine the predictive values of serial posttransplant blood cyclosporine trough (C(0)) concentrations to minimize the risk for a first rejection episode compared with 2-hour postdose (C(2)) drug concentrations. The final aim of the study was to identify a concentration range for the best predictive pharmacokinetic parameter that should be targeted to reduce the risk of rejection. This possibility was explored in 334 de novo kidney transplant recipients who participated in the prospective, multicenter Mycophenolate Steroid-Sparing Trial. Among measurements performed during the first 6 months postsurgery, cyclosporine C(0) levels measured early after transplantation were the strongest predictor of acute graft rejection. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while patients with levels lower than 300 ng/mL showed a more than double risk. Cyclosporine trough values predicted allograft rejection with an accuracy of 74%, while C(2) levels had no predictive value. These findings underline the need to target cyclosporine therapy early posttransplant to modulate T-cell activation.     

Diffusion-weighted MR imaging in monitoring the effect of a vascular targeting agent on rhabdomyosarcoma in rats

PURPOSE: To evaluate diffusion-weighted magnetic resonance (MR) imaging for monitoring tumor response in rats after administration of combretastatin A4 phosphate. MATERIALS AND METHODS: Study protocol was approved by local ethical committee for animal care and use. Rhabdomyosarcomas implanted subcutaneously in both flanks of 17 rats were evaluated with 1.5-T MR unit by using four-channel wrist coil. Transverse T2-weighted fast spin-echo sequences, T1-weighted spin-echo sequences before and after gadodiamide administration, and transverse echo-planar diffusion-weighted MR examinations were performed before, 1 and 6 hours, and 2 and 9 days after intraperitoneal injection of vascular targeting agent (combretastatin A4 phosphate, 25 mg/kg). Apparent diffusion coefficient (ADC) was automatically calculated from diffusion-weighted MR imaging findings. These findings were compared with histopathologic results at each time point. For statistical analysis, paired Student t tests with Bonferroni correction for multiple testing were used. RESULTS: T1-weighted images before combretastatin administration showed enhancement of solid tumor tissue but not of central necrosis. At 1 and 6 hours after combretastatin injection, enhancement of solid tissue disappeared almost completely, with exception of small peripheral rim. At 2 and 9 days after combretastatin injection, enhancement progressively reappeared in tumor periphery. ADC, however, showed decrease early after combretastatin injection ([1.26 +/- 0.16]x 10(-3) mm2/sec before, [1.18 +/- 0.17]x 10(-3) mm2/sec 1 hour after [P=.0005] and [1.08 +/- 0.14]x 10(-3) mm(2)/sec 6 hours after [P=.0007] combretastatin A4 phosphate injection), histologically corresponding to vessel congestion and vascular shutdown in periphery but no necrosis. An increase of ADC ([1.79 +/- 0.13]x 10(-3) mm2/sec) (P <.0001) 2 days after combretastatin A4 phosphate injection was paralleled by progressive histologic necrosis. A significant (P <.0001) decrease in ADC 9 days after treatment ([1.41 +/- 0.15]x 10(-3) mm2/sec) corresponded to tumor regrowth. CONCLUSION: In addition to basic relaxation-weighted MR imaging and postgadolinium T1-weighted MR imaging to enable prompt detection of vascular shutdown, diffusion-weighted MR imaging was used to discriminate between nonperfused but viable and necrotic tumor tissues for early monitoring of therapeutic effects of vascular targeting agent.     

Stimulatory effect of antidepressants on the production of IL-6

A body of evidence indicates that the therapeutic activity of antidepressants is connected with their modulatory effect on the inflammatory response system and cell-mediated immunity. The present study was carried out to examine the effects of antidepressant agents, such as imipramne, venlafaxine, l-5-hydroxytryptophan, fluoxetine and a combination of l-5-hydroxytryptophan and fluoxetine, on the production of the pleotrophic cytokines TNF-alpha and IL-6. Diluted whole blood from fluoxetine-treated patients with treatment-resistant depression (TRD) (mean age: 50.6+/-3.9 years), age-matched healthy controls (mean age: 51.6+/-1.7 years) and younger healthy volunteers (mean age: 35.4+/-1.7 years) was stimulated with phytohemagglutinin (PHA) and lipopolysaccharide (LPS) for 48 h with or without incubation with the antidepressants at 10(-6) and 10(-5) M. The major findings of this study are: (1). imipramine and venlafaxine (at the higher concentration), 5-HTP (at lower and higher concentrations) and a combination of 5-HTP and fluoxetine (both at the lower concentration) increased the production of IL-6; (2). all drugs used did not affect TNF-alpha production. IL-6 production was significantly higher in depressed patients than in age-matched volunteers, whereas TNF-alpha production was significantly higher in older volunteers than in younger ones. We speculate that the therapeutic activity of these antidepressants is at least partly connected with their effect on the cytokine network and IL-6 production.     

Decreased CD40 ligand induction in CD4 T cells and dysregulated IL-12 production during HIV infection.

During HIV infection various cytokines are overproduced in early stages, whereas in advanced disease cytokines of the T helper 1 type (e.g. interferon-gamma (IFN-gamma)) are selectively deficient. During antigenic stimulation, the production of type-1 cytokines is enhanced by IL-12, secreted by antigen-presenting cells (APC) after their interaction with activated CD4 T cells. Two factors are essential in this process: priming APC with IFN-gamma and triggering the CD40 receptor on APC by CD40 ligand (CD40L). In view of the importance of this pathway, we compared its regulation in HIV-infected and control subjects. After cross-linking of the T cell receptor (TCR)/CD3 complex, the proportional expression of CD40L was similar on CD4+ T cells from controls and from patients with high circulating CD4 T counts (> 500/microl), but CD40L up-regulation was significantly reduced in patients with more advanced disease. Simultaneous triggering of the costimulatory receptor CD28 on T cells through its natural ligand CD80 partly corrected the CD40L defect in patients with intermediate CD4 T counts (200-500), but not in AIDS patients. Early production of IFN-gamma was preserved in lymphocytes from HIV+ patients. The expression of CD40 on peripheral monocytes from HIV+ subjects was increased in a disease stage-related fashion. Stimulation of mononuclear cells through cell-bound CD40L and soluble IFN-gamma induced significantly higher IL-12 in cultures from patients with > 200 circulating CD4 T cells, whereas IL-12 production was marginally decreased in cultures from patients with < 200 CD4 T cells, compared with healthy control cultures. In conclusion, our data suggest that impaired CD40L induction on CD4 T cells contributes to deficient type-1 responses through decreased IL-12 production in AIDS infection, whereas enhanced CD40-mediated IL-12 production in less advanced stages might contribute to increased levels of various cytokines in early disease     

Semen parameters in a fertile versus subfertile population: a need for change in the interpretation of semen testing

This prospectively designed study was conducted to compare a fertile and a subfertile population so as to define normal values for different semen parameters. Semen analyses were performed according to the World Health Organization (WHO) guidelines, except for sperm morphology (strict criteria). In the fertile population (n = 144), all patients had recently achieved pregnancy, within 12 months of unprotected coitus. As subfertile controls we examined semen samples from 143 consecutive men attending our infertility clinic during the same study period. Couples with tubal factor infertility and/or ovulatory disorders were excluded from our study. Using receiver operating characteristic (ROC) curve analysis we determined the diagnostic potential and cut-off values for single and combined sperm parameters. Sperm morphology scored best, with a value of 78% (area under the ROC curve). Summary statistics showed a shift towards abnormality for most semen parameters in the subfertile population. Using the 10th percentile of the fertile population as the cut-off value, the following results were obtained: 14.3 x 10(6)/ml for sperm concentration, 28% for progressive motility and 5% for sperm morphology. Using ROC analysis, cut-off values were 34 x 10(6)/ml, 45% and 10% respectively. Cut-off values for normality were different from those described in the WHO guidelines. Routine bacterial and non- bacterial cultures turned out to be of little prognostic value.      

Comparison of visual grading and free-response ROC analyses for assessment of image-processing algorithms in digital mammography

Objective

To compare two methods for assessment of image-processing algorithms in digital mammography: free-response receiver operating characteristic (FROC) for the specific task of microcalcification detection and visual grading analysis (VGA).

Methods

The FROC study was conducted prior to the VGA study reported here. 200 raw data files of low breast density (Breast Imaging–Reporting and Data System I–II) mammograms (Novation DR, Siemens, Germany)—100 of which abnormal—were processed by four image-processing algorithms: Raffaello (IMS, Bologna, Italy), Sigmoid (Sectra, Linköping, Sweden), and OpView v. 2 and v. 1 (Siemens, Erlangen, Germany). Four radiologists assessed the mammograms for the detection of microcalcifications. 8 months after the FROC study, a subset (200) of the 800 images was reinterpreted by the same radiologists, using the VGA methodology in a side-by-side approach. The VGA grading was based on noise, saturation, contrast, sharpness and confidence with the image in terms of normal structures. Ordinal logistic regression was applied; OpView v. 1 was the reference processing algorithm.

Results

In the FROC study all algorithms performed better than OpView v. 1. From the current VGA study and for confidence with the image, Sigmoid and Raffaello were significantly worse (p<0.001) than OpView v. 1; OpView v. 2 was significantly better (p=0.01). For the image quality criteria, results were mixed; Raffaello and Sigmoid for example were better than OpView v. 1 for sharpness and contrast (although not always significantly).

Conclusion

VGA and FROC discordant results should be attributed to the different clinical task addressed.

Advances in knowledge

The method to use for image-processing assessment depends on the clinical task tested.Image processing applied in two-dimensional digital mammography has been suggested as a means of improving image quality, especially for patients with dense breast tissue [1-6]. In practice, edge enhancement, histogram equalisation and other greyscale adjustments [3,4] are applied that alter the pixel values of the images in order to enhance the conspicuity of relevant findings like masses and microcalcifications. The algorithms may vary substantially among different vendors and there is no consensus on what processing algorithm is considered optimal among radiologists [4]. The process by which image-processing algorithms and settings are optimised often remains undocumented, and testing of algorithms is neglected in any European acceptance protocol for digital mammography systems [7]. Whether image processing provides improved diagnostic accuracy or simply improves the subjective appearance of images deserves further study.With the advent of new technologies such as digital breast tomosynthesis, manufacturers have been and are introducing even more complex image processing and (iterative) reconstruction. Many researchers are studying the effects of such algorithms on clinical performance [8-13]. In most of these studies image quality has been quantified using physical measurements [8,9,13] (such as noise, signal-to-noise ratio, detective quantum efficiency, modulation transfer function) or psychophysical measurements [10,11] (using, for example, contrast–detail phantoms). Although physical methods are of fundamental importance in describing the image quality, establishing the link between physical image quality measures and clinical utility has been pursued for decades and their relationship is not yet fully understood [14,15].Receiver operating characteristic (ROC) analysis [16] and its location-specific variants [17-19] are currently considered the best methods to quantify and report diagnostic performance: they measure the ability of an observer to detect and correctly interpret pathological structures, such as microcalcifications and masses in a mammogram. Unfortunately, these methods require a large number of patient images and a large number of pathological lesions to reach a sufficient statistical power; moreover, the true health state of the patient must be known to classify an image as normal or abnormal, requiring a follow-up of typically 1 year to confirm benign and normal cases. Further, the cases need to be subtle so that false positives occur during the image interpretation. These requirements make the measurement of clinical performance difficult in practice and very time consuming. ROC analysis is typically performed at the introduction of new imaging modalities; for the evaluation of more subtle updates in a technology, the required effort may be considered excessive.A simpler method has been published by the European Commission (CEC) [20] and is based upon the scoring of image quality by inspecting normal anatomical structures; good visibility of these (normal) structures on a radiograph is considered to define appropriate image quality and accurate diagnosis. The set of anatomical criteria is specific for the given type of examination [20-22], and visual grading analysis (VGA) is typically applied to evaluate them. Images have to be graded with an absolute score by a number of observers or alternatively one can use the side-by-side approach, which involves simultaneous viewing of two images, and the score is meant to express the comparison of the two images. The number of studies using this approach has increased in the past few years [15,23-27].Correlation between VGA experiments and more objective ROC studies has previously been investigated, but the results of the few published studies are contradictory [28-30]. Pilgram et al [28] found a strong correlation between diagnostic performance and the subjective evaluation of image quality on the diagnosis of craniosynostosis. They studied in detail the responses of one observer, who read radiographs having different image quality (obtained with three different methods) for a set of patients with this diagnosis and found that the increase in diagnostic performance resulted primarily from increased specificity, suggesting that, when image quality is being evaluated, specificity and the evaluation of normal structures should be the focus of attention. In the studies of Tingberg et al [29,30], the influence of different characteristic curves on the diagnostic quality of radiographs of the lumbar spine and the chest evaluated with both VGA and free-response forced error (FFE) (an ROC variant) experiments showed mixed results. In the first experiment [29], lumbar spine images were manipulated by adding artificial lesions, and image processing was applied to simulate image appearance from three different screen–film combinations; VGA evaluation and FFE results were in good agreement. In the later paper [30], the authors found that images with greater contrast than the original had significantly improved image quality in the VGA study although this did not affect detectability in the FFE experiment, indicating that VGA has a stronger discriminative power than FFE. These contradictory results suggest that the influence of image processing on image interpretation justifies further research.The aim of this study was to investigate the role of a VGA method in the assessment of image-processing algorithms for digital mammography relative to an earlier applied free-response ROC (FROC) study that investigated the same algorithms but for the specific task of microcalcification detection.     

Validation of MTF measurement for digital mammography quality control

The modulation transfer function (MTF) describes the spatial resolution properties of imaging systems. In this work, the accuracy of our implementation of the edge method for calculating the presampled MTF was examined. Synthetic edge images with known MTF were used as gold standards for determining the robustness of the edge method. These images simulated realistic data from clinical digital mammography systems, and contained intrinsic system factors that could affect the MTF accuracy, such as noise, scatter, and flat-field nonuniformities. Our algorithm is not influenced by detector dose variations for MTF accuracy up to 1/2 the sampling frequency. We investigated several methods for noise reduction, including truncating the supersampled line spread function (LSF), windowing the LSF, applying a local exponential fit to the LSF, and applying a monotonic constraint to the supersampled edge spread function. Only the monotonic constraint did not introduce a systematic error; the other methods could result in MTF underestimation. Overall, our edge method consistently computed MTFs which were in good agreement with the true MTF. The edge method was then applied to images from a commercial storage-phosphor based digital mammography system. The calculated MTF was affected by the size (sides of 2.5, 5, or 10 cm) and the composition (lead or tungsten) of the edge device. However, the effects on the MTF were observed only with regard to the low frequency drop (LFD). Scatter nonuniformity was dependent on edge size, and could lead to slight underestimation of LFD. Nevertheless, this negative effect could be minimized by using an edge of 5 cm or larger. An edge composed of lead is susceptible to L-fluorescence, which causes overestimation of the LFD. The results of this work are intended to underline the need for clear guidelines if the MTF is to be given a more crucial role in acceptance tests and routine assessment of digital mammography systems: the MTF algorithm and edge object test tool need to be publicly validated.