Stigma and public attitudes toward euthanasia or assisted suicide for psychiatric conditions: results from a general population survey in Germany.

BACKGROUND: With growing numbers of countries legalizing euthanasia or assisted suicide (EAS), there is a debate as to whether EAS should also be available to people with severe, treatment-resistant mental illness. Excluding mental illness as a legitimate reason to receive EAS has been framed as discriminating against people with mental illness. AIMS: We examine whether approval or opposition to psychiatric EAS are related to stigma toward people with mental illness. METHOD: We asked a representative sample of the general population in Germany (N = 1515) whether they would approve of EAS for someone with severe, treatment-resistant mental illness. Stigma was assessed with the Value-Based Stigma Inventory (VASI), addressing rejection of people with mental illness in relation to different personal values. RESULTS: A total of 19% of the German population approved of psychiatric EAS. Higher stigma scores were associated with greater approval of EAS (Spearman rank correlation coefficient, 0.28; P < 0.001). This association held true when controlling for sociodemographic variables. It was strongest for stigma related to perceived threats to one's security, reputation and meritocratic values. CONCLUSIONS: Our results highlight that, although opposing psychiatric EAS is sometimes framed as discriminatory, approval of psychiatric EAS might also carry hidden, stigmatising motives. To avoid any unintended negative consequences for people with severe, treatment-resistant mental illness, any legislation on psychiatric EAS needs to be crafted with particular caution.

Public attitudes towards protecting the human rights of people with mental illness: a scoping review and data from a population trend study in Germany.

The human rights of people with mental illness are constantly threatened. We conduct a scoping review showing how public attitudes towards protecting human rights have so far been examined and providing an overview of our present knowledge of these attitudes, and present novel findings from a trend study in Germany over nine years, reporting attitudes elicited in 2020 and examining whether these attitudes have changed since 2011. Few studies address attitudes towards human rights explicitly, but several studies contain single items on either first generation human rights, mainly concerning involuntary admission, or civil liberties like the right to vote, or second generation human rights, mainly with regard to funding for healthcare, but also for example regarding career choice. Recent data from Germany showed little improvement in attitudes towards protecting human rights over the last decade and particularly high support for restricting job opportunities for people with mental illness. Although generally, most restrictions were supported by a minority of respondents only, both our data and our scoping review indicate substantial support for several restrictions in several countries, showing that public attitudes pose a challenge to the human rights of persons with mental illness. We discuss possible lines of future research.

Mammillary body and hypothalamic volumes in mood disorders.

We have previously reported an in vivo enlargement of the left hypothalamus in mood disorders using 7 T magnetic resonance imaging. The aim of this follow-up study was to find out whether the hypothalamic volume difference may be located in the mammillary bodies (MB) rather than being widespread across the hypothalamus. We developed and evaluated a detailed segmentation algorithm that allowed a reliable segmentation of the MBs, and applied it to 20 unmedicated (MDDu) and 20 medicated patients with major depressive disorder, 21 medicated patients with bipolar disorder, and 23 controls. 20 out of 23 healthy controls were matched to the MDDu. We tested for group differences in MB and hypothalamus without MB (HTh) volumes using analyses of covariance. Associations between both volumes of interest were analysed using bivariate and partial correlations. In contrast to postmortem findings, we found no statistically significant differences of the MB volumes between the study groups. Left HTh volumes differed significantly across the study groups after correction for intracranial volume (ICV) and for ICV and sex. Our result of an HTh enlargement in mood disorders was confirmed by a paired t-test between the matched pairs of MDDu and healthy controls using the native MB and HTh volumes. In the whole sample, MB volumes correlated significantly with the ipsilateral HTh volumes. Our results indicate a structural relationship between both volumes, and that our previous in vivo finding of a hypothalamus enlargement does not extend to the MB, but is limited to the HTh. The enlargement is more likely related to the dysregulation of the HPA axis than to cognitive dysfunctions accompanying mood disorders.

Hypothalamic volume in pedophilia with or without child sexual offense.

The hypothalamus regulates sexual behavior and is simultaneously associated with aggression and violence. Consequently, this brain region is relevant in research of pedophilia and child sexual offenses (CSO). The distinction between these two phenomena is of great importance and was the object of consideration of this study. We analyzed exclusively men, including 73 pedophilic offenders who committed CSO, an equal number of people with pedophilia but without such offenses, and 133 non-pedophilic, non-offending subjects who formed the control group. All data were collected in a multicenter in vivo study and analyzed using a semi-automated segmentation algorithm for 3-Tesla magnetic resonance images. Men with pedophilia who committed CSO on average had a 47 mm3 smaller hypothalamus per side than people without committed CSO. This effect was driven by both the group of non-offending people with pedophilia and the control group. By contrast, the exploratory comparison of pedophilic persons without CSO with the control group showed no significant difference. The present study demonstrates a deviant hypothalamic structure as a neurobiological correlate of CSO in pedophiles, but not in people with pedophilia who have not committed CSO. Thus, it strengthens the argument to distinguish between sexual offending and paraphilic sexual preferences.

Changes in continuum beliefs for depression and schizophrenia in the general population 2011-2020: a widening gap.

PURPOSE: The public discourse about mental health and mental illness seems to have become more open over the last decade, giving rise to the hope that symptoms of mental illness have become more relatable. We examine whether continuum beliefs regarding schizophrenia and depression have increased on a population level over a period of 9 years, and whether notions of unfamiliarity and incomprehensibility have decreased. METHODS: In 2011 (n = 2455) and 2020 (n = 3042), two methodologically identical cross-sectional population surveys were conducted in Germany. After the presentation of an unlabeled case vignette depicting someone with schizophrenia or depression, we asked about continuum beliefs, perceived unfamiliarity and perceived incomprehensibility of the person described. RESULTS: Multinomial logit models holding sociodemographic variables fixed at their means for both surveys showed that agreement with continuum beliefs increased in depression from 43 to 46% [change 4%; 95% confidence interval (CI) 0; 8], but decreased in schizophrenia from 26 to 20% (change - 6%, 95% CI - 9; - 3). Unfamiliarity (change - 4%; 95% CI - 7; 0) and incomprehensibility (change - 7%, 95% CI - 10; - 4) decreased for depression, while remaining largely unchanged for schizophrenia. CONCLUSION: An already pronounced gap in the perception of both disorders with regard to continuity of symptom experiences and perceived otherness further widened over the last decade. While the public's increasing familiarity with symptoms of depression might be further aided by using continuum beliefs as part of anti-stigma messages and awareness campaigns, promulgating continuity models for schizophrenia seems more challenging.

Changes in mental illness stigma over 30 years - Improvement, persistence, or deterioration?

BACKGROUND: Large efforts have been made to erase the stigma of mental illness, but it is unclear whether they have succeeded on a population level. We examine how attitudes toward people with depression or schizophrenia have evolved in Germany since 1990, and whether there are different developments for both disorders. METHODS: Using data from the three decades, four wave repeated cross-sectional representative population study in the "old" (western) states in Germany with surveys in 1990 (n = 2,044), 2001 (n = 4,005), 2011 (n = 1,984), and 2020 (n = 2,449), we calculate time-trends for social distance and emotional reactions toward someone with major depression or acute schizophrenia. RESULTS: Social distance worsened in six out of seven situations for schizophrenia, whereas improving in two out of seven situations for depression. Emotions related to fear and uneasiness increased for schizophrenia, whereas tending to decrease for depression. Pro-social reactions like the desire to help increased for depression, but decreased for schizophrenia. Initially observed differences, favoring depression over schizophrenia, widened over the 30-year study period. For schizophrenia, the biggest negative changes occurred between 1990 and 2001, whereas some improvements with regard to depression occurred more recently. CONCLUSION: Contrary to expectations, stigma has become more severe regarding acute schizophrenia in Germany over the last 30 years, whereas only slightly improving for depression. The apparent normalization of mental health problems seems not to directly translate into improving attitudes toward people with severe mental illness. Re-focusing of anti-stigma efforts on people with severe mental illness seems necessary.

Stigma as a barrier to addressing childhood trauma in conversation with trauma survivors: A study in the general population.

Victims of childhood trauma report shame and anticipation of stigma, leading to non-disclosure and avoidance of help. Stigma is potentially aggravating the mental health consequences of childhood trauma. So far there is no comprehensive study examining stigma toward adult survivors of various forms of childhood trauma, and it is unclear whether stigma interferes with reaching out to affected individuals. In a vignette study based on a representative sample of the German general population (N = 1320; 47.7% male) we randomly allocated participants to brief case vignettes pertaining to past childhood sexual/physical abuse or accidents, and adult physical abuse. Stigma was elicited by applying the Social Distance Scale, assessing respondents' attitudes/stereotypes toward the persons in the vignette and their reluctance to address the specific trauma in conversation. While one aim was to establish the prevalence of stigma toward persons with CT, we hypothesized that attitudes differ according to type of trauma. Of the respondents, 45% indicated they were unlikely to reach out to a victim of childhood sexual abuse, 38% to a victim of childhood physical abuse, 31% to someone reporting a childhood accident and 25% to someone reporting adult physical abuse. Contrary to our expectations, childhood sexual abuse did not consistently elicit more stigma than childhood physical abuse in Krukall-Wallis tests. Equally, childhood interpersonal trauma did not consistently elicit more stigma than childhood accidental trauma. Structural equation modeling revealed social distance as mediator of the relationship between negative stereotypes and reluctance to address childhood trauma in conversation. Our analyses further revealed an ambiguous role of negative stereotypes in addressing childhood trauma in conversation with trauma victims, which has yet to be examined. There is evidence for stigma associated with having survived childhood trauma, which is interfering with offering help.

Continuum beliefs and mental illness stigma: a systematic review and meta-analysis of correlation and intervention studies.

BACKGROUND: Promulgating a continuum model of mental health and mental illness has been proposed as a way to reduce stigma by decreasing notions of differentness. This systematic review and meta-analysis examines whether continuum beliefs are associated with lower stigma, and whether continuum interventions reduce stigma. METHODS: Following a pre-defined protocol (PROSPERO: CRD42019123606), we searched three electronic databases (PubMed, Web of Science, and PsycINFO) yielding 6726 studies. After screening, we included 33 studies covering continuum beliefs, mental illness, and stigma. Of these, 13 studies were included in meta-analysis. RESULTS: Continuum beliefs are consistently associated with lower stigma. Interventions were effective at manipulating continuum beliefs but differ in their effects on stigmatising attitudes. CONCLUSIONS: We discuss whether and to what extent attitudes towards people with mental illness can be improved by providing information on a mental health-mental illness continuum. It appeared to be relevant whether interventions promoted a feeling of 'us' and a process of identification with the person with mental illness. We discuss implications for the design of future interventions.

A semi-automated algorithm for hypothalamus volumetry in 3 Tesla magnetic resonance images.

The hypothalamus, a small diencephalic gray matter structure, is part of the limbic system. Volumetric changes of this structure occur in psychiatric diseases, therefore there is increasing interest in precise volumetry. Based on our detailed volumetry algorithm for 7 Tesla magnetic resonance imaging (MRI), we developed a method for 3 Tesla MRI, adopting anatomical landmarks and work in triplanar view. We overlaid T1-weighted MR images with gray matter-tissue probability maps to combine anatomical information with tissue class segmentation. Then, we outlined regions of interest (ROIs) that covered potential hypothalamus voxels. Within these ROIs, seed growing technique helped define the hypothalamic volume using gray matter probabilities from the tissue probability maps. This yielded a semi-automated method with short processing times of 20-40 min per hypothalamus. In the MRIs of ten subjects, reliabilities were determined as intraclass correlations (ICC) and volume overlaps in percent. Three raters achieved very good intra-rater reliabilities (ICC 0.82-0.97) and good inter-rater reliabilities (ICC 0.78 and 0.82). Overlaps of intra- and inter-rater runs were very good (≥ 89.7%). We present a fast, semi-automated method for in vivo hypothalamus volumetry in 3 Tesla MRI.

Pattern recognition receptors mediate pro-inflammatory effects of extracellular mitochondrial transcription factor A (TFAM).

Neuroinflammation is a common pathogenic mechanism for a number of neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Microglia, the immune cells of the brain, contribute to the onset and progression of the neuroinflammation observed in these diseases. Microglia become activated and initiate an inflammatory response by interacting with a diverse set of molecules, including the group of endogenous proteins released upon cell damage, termed damage-associated molecular patterns (DAMPs). One of these molecules, mitochondrial transcription factor A (TFAM), has been shown to induce pro-inflammatory and cytotoxic responses of microglia in vitro. Here, we demonstrate that TFAM injected into the cisterna magna of male Sprague-Dawley rats upregulates (i) the expression of monocyte chemotactic protein (MCP)-1, interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α and nuclear factor-kappa B inhibitor alpha (NF-κBIA) in the hippocampus; (ii) the expression of MCP-1, IL-1ß and TNF-α in the frontal cortex; and (iii) IL-1ß protein concentration in both these brain regions. These same inflammatory mediators are upregulated in isolated rat microglia following their in vitro exposure to extracellular TFAM. Blocking the receptor for advanced glycation endproducts (RAGE) and the macrophage antigen complex (Mac)-1 by specific antibodies inhibited the TFAM-induced secretion of MCP-1 by THP-1 monocytic cells, which were used to model human microglia. Our data support the hypothesis that extracellular TFAM can interact with RAGE and Mac-1 to function as a DAMP that causes pro-inflammatory microglial activation. Blocking this interaction may represent a potential target for attenuating the neuroinflammation observed in neurodegenerative diseases.

Intensity standardisation of 7T MR images for intensity-based segmentation of the human hypothalamus.

The high spatial resolution of 7T MRI enables us to identify subtle volume changes in brain structures, providing potential biomarkers of mental disorders. Most volumetric approaches require that similar intensity values represent similar tissue types across different persons. By applying colour-coding to T1-weighted MP2RAGE images, we found that the high measurement accuracy achieved by high-resolution imaging may be compromised by inter-individual variations in the image intensity. To address this issue, we analysed the performance of five intensity standardisation techniques in high-resolution T1-weighted MP2RAGE images. Twenty images with extreme intensities in the GM and WM were standardised to a representative reference image. We performed a multi-level evaluation with a focus on the hypothalamic region-analysing the intensity histograms as well as the actual MR images, and requiring that the correlation between the whole-brain tissue volumes and subject age be preserved during standardisation. The results were compared with T1 maps. Linear standardisation using subcortical ROIs of GM and WM provided good results for all evaluation criteria: it improved the histogram alignment within the ROIs and the average image intensity within the ROIs and the whole-brain GM and WM areas. This method reduced the inter-individual intensity variation of the hypothalamic boundary by more than half, outperforming all other methods, and kept the original correlation between the GM volume and subject age intact. Mixed results were obtained for the other four methods, which sometimes came at the expense of unwarranted changes in the age-related pattern of the GM volume. The mapping of the T1 relaxation time with the MP2RAGE sequence is advertised as being especially robust to bias field inhomogeneity. We found little evidence that substantiated the T1 map's theoretical superiority over the T1-weighted images regarding the inter-individual image intensity homogeneity.

Habenula volume increases with disease severity in unmedicated major depressive disorder as revealed by 7T MRI.

The habenula is a paired epithalamic structure involved in the pathogenesis of major depressive disorder (MDD). Evidence comes from its impact on the regulation of serotonergic and dopaminergic neurons, the role in emotional processing and studies on animal models of depression. The present study investigated habenula volumes in 20 unmedicated and 20 medicated MDD patients and 20 healthy controls for the first time by applying a triplanar segmentation algorithm on 7 Tesla magnetic resonance (MR) whole-brain T1 maps. The hypothesis of a right-side decrease of habenula volumes in the MDD patients was tested, and the relationship between volumetric abnormalities and disease severity was exploratively investigated. Absolute and relative total and hemispheric habenula volumes did not differ significantly between the three groups. In the patients with short duration of disease for which medication effects could be ruled out, significant correlations were found between bilateral habenula volumes and HAMD-17- and BDI-II-related severities. In the medicated patients, this positive relationship disappeared. Our findings suggest an involvement of habenula pathology in the beginning of MDD, while general effects independent of severity or stage of disease did not occur. Our findings warrant future combined tractographic and functional investigation using ultra-high-resolution in vivo MR imaging.

Elucidating the link between the modifiable risk factors of Alzheimer's disease and neuroinflammation.

Increased worldwide longevity through medical interventions, although beneficial, has allowed the age-related Alzheimer's disease (AD) to become an epidemic of the 21st century. AD pathology involves adverse activation of microglia, the immune cells of the brain and resulting chronic neuroinflammation. Certain diets, physical inactivity and Type 2 diabetes mellitus have been identified as the risk factors for developing AD, which may increase the risk of AD by neuroimmune mechanisms primarily through the overactivation of microglia. Thus, modifying these risk factors may represent an alternative therapeutic strategy for lowering the incidence of AD. We highlight the link between select modifiable risk factors and neuroimmune mechanisms, and demonstrate that by controlling microglial activation and neuroinflammation the prevalence of AD may be decreased.

A new look at auranofin, dextromethorphan and rosiglitazone for reduction of glia-mediated inflammation in neurodegenerative diseases.

Neurodegenerative disorders including Alzheimer's disease are characterized by chronic inflammation in the central nervous system. The two main glial types involved in inflammatory reactions are microglia and astrocytes. While these cells normally protect neurons by providing nutrients and growth factors, disease specific stimuli can induce glial secretion of neurotoxins. It has been hypothesized that reducing glia-mediated inflammation could diminish neuronal loss. This hypothesis is supported by observations that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) is linked with lower incidences of neurodegenerative disease. It is possible that the NSAIDs are not potent enough to appreciably reduce chronic neuroinflammation after disease processes are fully established. Gold thiol compounds, including auranofin, comprise another class of medications effective at reducing peripheral inflammation. We have demonstrated that auranofin inhibits human microglia- and astrocyte-mediated neurotoxicity. Other drugs which are currently used to treat peripheral inflammatory conditions could be helpful in neurodegenerative disease. Three different classes of anti-inflammatory compounds, which have a potential to inhibit neuroinflammation are highlighted below.

Microparticles: a new perspective in central nervous system disorders.

Microparticles (MPs) are a heterogeneous population of small cell-derived vesicles, ranging in size from 0.1 to 1 µ m. They contain a variety of bioactive molecules, including proteins, biolipids, and nucleic acids, which can be transferred between cells without direct cell-to-cell contact. Consequently, MPs represent a novel form of intercellular communication, which could play a role in both physiological and pathological processes. Growing evidence indicates that circulating MPs contribute to the development of cancer, inflammation, and autoimmune and cardiovascular diseases. Most cell types of the central nervous system (CNS) have also been shown to release MPs, which could be important for neurodevelopment, CNS maintenance, and pathologies. In disease, levels of certain MPs appear elevated; therefore, they may serve as biomarkers allowing for the development of new diagnostic tools for detecting the early stages of CNS pathologies. Quantification and characterization of MPs could also provide useful information for making decisions on treatment options and for monitoring success of therapies, particularly for such difficult-to-treat diseases as cerebral malaria, multiple sclerosis, and Alzheimer's disease. Overall, studies on MPs in the CNS represent a novel area of research, which promises to expand the knowledge on the mechanisms governing some of the physiological and pathophysiological processes of the CNS.

Mitochondrial transcription factor A (Tfam) is a pro-inflammatory extracellular signaling molecule recognized by brain microglia.

Microglia represent mononuclear phagocytes in the brain and perform immune surveillance, recognizing a number of signaling molecules released from surrounding cells in both healthy and pathological situations. The microglia interact with several damage-associated molecular pattern molecules (DAMPs) and recent data indicate that mitochondrial transcription factor A (Tfam) could act as a specific DAMP in peripheral tissues. This study tested the hypothesis that extracellular Tfam induces pro-inflammatory and cytotoxic responses of the microglia. Three different types of human mononuclear phagocytes were used to model human microglia: human peripheral blood monocytes from healthy donors, human THP-1 monocytic cells, and human primary microglia obtained from autopsy samples. When combined with interferon (IFN)-γ, recombinant human Tfam (rhTfam) induced secretions that were toxic to human SH-SY5Y neuroblastoma cells in all three models. Similar cytotoxic responses were observed when THP-1 cells and human microglia were exposed to human mitochondrial proteins in the presence of IFN-γ. rhTfam alone induced expression of pro-inflammatory cytokines interleukin (IL)-1ß, IL-6 and IL-8 by THP-1 cells. This induction was further enhanced in the presence of IFN-γ. Upregulated secretion of IL-6 in response to rhTfam plus IFN-γ was confirmed in primary human microglia. Use of specific inhibitors showed that the rhTfam-induced cytotoxicity of human THP-1 cells depended partially on activation of c-Jun N-terminal kinase (JNK), but not p38 mitogen-activated protein kinase (MAPK). Overall, our data support the hypothesis that, in the human brain, Tfam could act as an intercellular signaling molecule that is recognized by the microglia to cause pro-inflammatory and cytotoxic responses.

Development and evaluation of an algorithm for the computer-assisted segmentation of the human hypothalamus on 7-Tesla magnetic resonance images.

Post mortem studies have shown volume changes of the hypothalamus in psychiatric patients. With 7T magnetic resonance imaging this effect can now be investigated in vivo in detail. To benefit from the sub-millimeter resolution requires an improved segmentation procedure. The traditional anatomical landmarks of the hypothalamus were refined using 7T T1-weighted magnetic resonance images. A detailed segmentation algorithm (unilateral hypothalamus) was developed for colour-coded, histogram-matched images, and evaluated in a sample of 10 subjects. Test-retest and inter-rater reliabilities were estimated in terms of intraclass-correlation coefficients (ICC) and Dice's coefficient (DC). The computer-assisted segmentation algorithm ensured test-retest reliabilities of ICC≥.97 (DC≥96.8) and inter-rater reliabilities of ICC≥.94 (DC = 95.2). There were no significant volume differences between the segmentation runs, raters, and hemispheres. The estimated volumes of the hypothalamus lie within the range of previous histological and neuroimaging results. We present a computer-assisted algorithm for the manual segmentation of the human hypothalamus using T1-weighted 7T magnetic resonance imaging. Providing very high test-retest and inter-rater reliabilities, it outperforms former procedures established at 1.5T and 3T magnetic resonance images and thus can serve as a gold standard for future automated procedures.

Diffusion imaging-based subdivision of the human hypothalamus: a magnetic resonance study with clinical implications.

The hypothalamus and its subdivisions are involved in many neuropsychiatric conditions such as affective disorders, schizophrenia, or narcolepsy, but parcellations of hypothalamic subnuclei have hitherto been feasible only with histological techniques in postmortem brains. In an attempt to map subdivisions of the hypothalamus in vivo, we analyzed the directionality information from high-resolution diffusion-weighted magnetic resonance images of healthy volunteers. We acquired T1-weighted and diffusion-weighted scans in ten healthy subjects at 3 T. In the T1-weighted images, we manually delineated an individual mask of the hypothalamus in each subject and computed in the co-registered diffusion-weighted images the similarity of the principal diffusion direction for each pair of mask voxels. By clustering the similarity matrix into three regions with a k-means algorithm, we obtained an anatomically coherent arrangement of subdivisions across hemispheres and subjects. In each hypothalamus mask, we found an anterior region with dorsoventral principal diffusion direction, a posteromedial region with rostro-caudal direction, and a lateral region with mediolateral direction. A comparative analysis with microstructural hypothalamus parcellations from the literature reveals that each of these regions corresponds to a specific group of hypothalamic subnuclei as defined in postmortem brains. This is to our best knowledge the first in vivo study that attempts a delineation of hypothalamic subdivisions by clustering diffusion-weighted magnetic resonance imaging data. When applied in a larger sample of neuropsychiatric patients, a structural analysis of hypothalamic subnuclei should contribute to a better understanding of the pathogenesis of neuropsychiatric conditions such as affective disorders.

Structural studies of the hypothalamus and its nuclei in mood disorders.

A large body of evidence indicates that the hypothalamus is involved in pathogenetic mechanisms of mood disorders. It has been suggested that functional abnormalities of the hypothalamus are associated with structural hypothalamic changes. Structural neuroimaging allows in vivo investigation of the hypothalamus that may shed light on the underlying pathogenetic mechanisms of unipolar and bipolar disorder. Clearly, the detection of subtle structural cerebral changes depends on the limitations of the neuroimaging technique used. Making a comprehensive database search, we reviewed the literature on hypothalamic macrostructure in affective disorders, addressing the specific question of what structural magnetic resonance imaging might be expected to show. Studies with convincing methodology, although rare, suggest a global volume decrease in the hypothalamus in affective disorders, a decrease which is not shown by the two specific nuclei investigated, the paraventricular and supraoptic nuclei. We discuss the implications of these findings and provide directions for future research.

Fever in the test tube--towards a human(e) pyrogen test.

The human whole blood IL-1 test exploits the reaction of monocytes/macrophages for the detection of pyrogens: human whole blood taken from healthy volunteers is incubated in the presence of the test sample in any form, be it a solution, a powder or even solid material. Pyrogenic contaminations initiate the release of the "endogenous pyrogen" Interleukin-1beta determined by ELISA after incubation. In order to understand any differences between the pyrogenic activity in this test and the existing live rabbit test (species differences versus aberrant response of the particular blood sample), the rabbit whole blood test was developed. This approach could also help to avoid the use of putatively infectious human blood for pyrogen testing in vitro.