Screening for chemicals with thyroid hormone-disrupting effects using zebrafish embryo.

Thyroid disruption is an increasingly recognized issue in the use and development of chemicals and new drugs, especially to help toxicologist to complement the reproductive and developmental toxicology information of chemicals. Still, adequate assessment methods are scarce and often suffer a trade-off between physiological relevance and labor- and cost-intensive assays. Here, we present a tiered approach for a medium-throughput screening of chemicals to identify their thyroid disrupting potential in zebrafish embryos as a New Approach Methodology (NAM). After identifying the maximum tolerated concentrations, we exposed zebrafish larvae to sub-adverse effect levels of the reference compounds benzophenone-2, bisphenol A, phenylthiourea, potassium perchlorate, propylthiouracil, and phloroglucinol to exclude any systemic toxicity. Applying the transgenic zebrafish line that carries a gene for the red fluorescence protein (Tg(tg:mCherry)) under the thyroglobulin promoter, we could identify the thyroid disrupting effects of the chemicals by a time and cost-effective image analysis measuring the fluorescence levels in the thyroid glands. Our observations could be confirmed by altered expression patterns of genes involved in the hypothalamus-pituitary-thyroid (HPT) axis. Finally, to anchor the observed thyroid disruption, we determined some changes in the Thyroid hormone levels of triiodothyronine (T3) and Thyroxine (T4) using a newly developed liquid chromatography mass spectrometric (LCMS) method. The presented approach carries the potential to extend the toolbox for legislative authorities and chemical producers for the assessment of thyroid-specific endocrine disruption and to overcome current challenges in the evaluation of endocrine disruptors.

Monro-Kellie Hypothesis: Increase of Ventricular CSF Volume after Surgical Closure of a Spinal Dural Leak in Patients with Spontaneous Intracranial Hypotension.

BACKGROUND AND PURPOSE: CSF loss in spontaneous intracranial hypotension disrupts a well-regulated equilibrium. We aimed to evaluate the volume shift between intracranial compartments in patients with spontaneous intracranial hypotension before and after surgical closure of the underlying spinal dural breach. MATERIALS AND METHODS: In total, 19 patients with spontaneous intracranial hypotension with a proved spinal CSF leak investigated at our institution between July 2014 and March 2017 (mean age, 41.8 years; 13 women) were included. Brain MR imaging-based volumetry at baseline and after surgery was performed with FreeSurfer. In addition, the spontaneous intracranial hypotension score, ranging from 0 to 9, with 0 indicating very low and 9 very high probability of spinal CSF loss, was calculated. RESULTS: Total mean ventricular CSF volume significantly increased from baseline (15.3 mL) to posttreatment MR imaging (18.0 mL), resulting in a mean absolute and relative difference, +2.7 mL and +18.8% (95% CI, +1.2 to +3.9 mL; P < .001). The change was apparent in the early follow-up (mean, 4 days). No significant change in mean total brain volume was observed (1136.9 versus 1133.1 mL, P = .58). The mean spontaneous intracranial hypotension score decreased from 6.9 ± 1.5 at baseline to 2.9 ± 1.5 postoperatively. CONCLUSIONS: Our study demonstrated a substantial increase in ventricular CSF volume in the early follow-up after surgical closure of the underlying spinal dural breach and may provide a causal link between spinal CSF loss and spontaneous intracranial hypotension. The concomitant decrease in the spontaneous intracranial hypotension score postoperatively implies the restoration of an equilibrium within the CSF compartment.

Brewer's yeast is a potent inducer of fever, sickness behavior and inflammation within the brain.

Brewer's yeast, derived from the yeast species Saccharomyces cerevisiae (S. cerevisiae), is commonly used for inducing pyrexia in pharmacological studies screening antipyretics in rats. Despite its widespread use, the peripheral and central inflammatory response associated with Brewer's yeast-induced fever and sickness behavior in rats has not been investigated. Thus, we injected male Sprague-Dawley rats (150-200 g) subcutaneously with a high (4 g/kg, n = 9), medium (2 g/kg, n = 5) or low (0.4 g/kg, n = 6) dose of Brewer's yeast solution or saline (0.9%, n = 6) and measured core body temperature, cage activity, food intake and body mass for six days after injection. Blood and brain samples were collected at 2, 8, 18 and 72 h after injection; n = 5-7 per time point. Brewer's yeast administration dose-dependently induced fever, lethargy, anorexia and body mass stunting that was accompanied by increased blood plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α and activation of inflammatory transcription factors (nuclear factor (NF) for interleukin-6, signal transducer and activator of transcription (STAT)-3, and NF-κB)) in the hypothalamus and circumventricular organs. The increased activation of transcription factors following Brewer's yeast administration was accompanied by increased hypothalamic mRNA expression of TNF-α, IL-1ß and IL-6 and rate-limiting enzymes for prostaglandin synthesis. Our results show that subcutaneous administration of S. cerevisae induces prolonged fever, anorexia and lethargy that is accompanied by a pronounced increase in the synthesis of pro-inflammatory cytokines, key prostaglandin synthesizing enzymes and transcription factors, in the periphery and brain.

Estimation of brain network ictogenicity predicts outcome from epilepsy surgery.

Surgery is a valuable option for pharmacologically intractable epilepsy. However, significant post-operative improvements are not always attained. This is due in part to our incomplete understanding of the seizure generating (ictogenic) capabilities of brain networks. Here we introduce an in silico, model-based framework to study the effects of surgery within ictogenic brain networks. We find that factors conventionally determining the region of tissue to resect, such as the location of focal brain lesions or the presence of epileptiform rhythms, do not necessarily predict the best resection strategy. We validate our framework by analysing electrocorticogram (ECoG) recordings from patients who have undergone epilepsy surgery. We find that when post-operative outcome is good, model predictions for optimal strategies align better with the actual surgery undertaken than when post-operative outcome is poor. Crucially, this allows the prediction of optimal surgical strategies and the provision of quantitative prognoses for patients undergoing epilepsy surgery.

Different effects of strength and endurance exercise training on COX-2 and mPGES expression in mouse brain are independent of peripheral inflammation.

Acute endurance exercise has been shown to modulate cyclooxygenase (COX)-2 expression, which is suggested to affect neuronal plasticity and learning. Here, we investigated the effect of regular strength and endurance training on cerebral COX-2 expression, inflammatory markers in the brain, and circulating cytokines. Male C57BL/6N mice were assigned to either a sedentary control group (CG), an endurance training group (EG; treadmill running for 30 min/day, 5 times/wk, 10 wk), or a strength training group (SG; strength training by isometric holding, same duration as EG). Four days after the last bout of exercise, blood and brain were collected and analyzed using real-time PCR, Western blot, and a multiplexed immunoassay. In EG, COX-2 mRNA expression in the cortex/hippocampus increased compared with CG. A significant increase of COX-2 protein levels was observed in both cortex/hippocampus and hypothalamus of mice from the SG. Nuclear factor (NF)κB protein levels were significantly increased in mice from both exercise groups (hypothalamus). A significant increase in the expression of microsomal prostaglandin E synthase (mPGES), an enzyme downstream of COX-2, was found in the hypothalamus of both the EG and SG. While most inflammatory factors, like IL-1α, IL-18, and IL-2, decreased after training, a positive association was found between COX-2 mRNA expression (cortex/hippocampus) and plasma IL-6 in the EG. Taken together, this study demonstrates that both endurance as well as strength training induces COX-2 expression in the cortex/hippocampus and hypothalamus of mice. A potential mediator of COX-2 expression after training might be circulating interleukin (IL)-6. However, further research is necessary to elucidate the role of inflammatory pathways on brain plasticity after training.

Effects of prostaglandin E2 on cells cultured from the rat organum vasculosum laminae terminalis and median preoptic nucleus.

The time course of the induction of enzymes responsible for the formation of prostaglandin E2 (PGE2) after an inflammatory insult, in relation to the concomitant febrile response, suggests that peripherally generated PGE2 is involved in the induction of the early phase of fever, while centrally produced PGE2 exerts pyrogenic capacities during the later stages of fever within the hypothalamic median preoptic nucleus (MnPO). The actions of peripherally derived PGE2 on the brain might occur at the level of the organum vasculosum laminae terminalis (OVLT), which lacks a tight blood-brain barrier and is implicated in fever, while the effects of PGE2 within the MnPO might interfere with glutamatergic neurotransmission within a recently characterized central efferent pathway for the activation of cold-defence reactions. Using the fura-2 ratio imaging technique we, therefore, measured changes of the intracellular Ca(2+)-concentration in primary neuroglial microcultures of rat OVLT and MnPO stimulated with PGE2 and/or glutamate. In cultures from the OVLT, as opposed to those derived from the MnPO, substantial numbers of neurons (8% of 385), astrocytes (19% of 645) and microglial cells (28% of 43) directly responded to PGE2 with a transient increase of intracellular Ca(2+). The most pronounced effect of PGE2 on cells from MnPO microcultures was its modulatory influence on the strength of glutamate-induced Ca(2+)-signals. In 72 out of 512 neurons and in 105 out of 715 astrocytes PGE2 significantly augmented glutamate-induced Ca(2+)-signals. About 30% of these neurons were GABAergic. These observations are in agreement with putative roles of peripheral PGE2 as a directly acting circulating agent at the level of the OVLT, and of central MnPO-intrinsic PGE2 as an enhancer of glutamatergic neurotransmission, which causes disinhibition of thermogenic heat production, a crucial component for the manifestation of fever. In microcultures from both brain sites investigated incubation with PGE2 significantly reduced the lipopolysaccharide-induced release of cytokines (tumor necrosis factor-α and interleukin-6) into the supernatant. PGE2, thus, seems to be involved in a negative feed-back loop to limit the strength of the brain inflammatory process and to play a dual role with pro- as well as anti-inflammatory properties.

Collective Modes and Structural Modulation in Ni-Mn-Ga(Co) Martensite Thin Films Probed by Femtosecond Spectroscopy and Scanning Tunneling Microscopy.

The origin of the martensitic transition in the magnetic shape memory alloy Ni-Mn-Ga has been widely discussed. While several studies suggest it is electronically driven, the adaptive martensite model reproduced the peculiar nonharmonic lattice modulation. We used femtosecond spectroscopy to probe the temperature and doping dependence of collective modes, and scanning tunneling microscopy revealed the corresponding static modulations. We show that the martensitic phase can be described by a complex charge-density wave tuned by magnetic ordering and strong electron-lattice coupling.

Intraperitoneal and subcutaneous injections of the TLR9 agonist ODN 1668 in rats: brain inflammatory responses are related to peripheral IL-6 rather than interferons.

Subcutaneous or intraperitoneal administration of Toll-like receptor (TLR)-9 agonist, ODN 1668 caused moderate fever and anorexia. In comparison to stimulation of other intracellular TLRs, activation of TLR9 did not result in pronounced peripheral induction of interferons, but rather induced interleukin-6. Expression of cytokines (TNFα, IL-1ß) and inducible forms of enzymes for prostaglandin E2 synthesis occurred in the brain, in conjunction with a moderate activation of the transcription factors STAT3 and NF-IL6 in brain endothelial cells. The lack of a septic-like state in ODN 1668-treated rats reinforces the therapeutic value of this drug.

Neuroimaging of epilepsy: lesions, networks, oscillations.

While analysis and interpretation of structural epileptogenic lesion is an essential task for the neuroradiologist in clinical practice, a substantial body of epilepsy research has shown that focal lesions influence brain areas beyond the epileptogenic lesion, across ensembles of functionally and anatomically connected brain areas. In this review article, we aim to provide an overview about altered network compositions in epilepsy, as measured with current advanced neuroimaging techniques to characterize the initiation and spread of epileptic activity in the brain with multimodal noninvasive imaging techniques. We focus on resting-state functional magnetic resonance imaging (MRI) and simultaneous electroencephalography/fMRI, and oppose the findings in idiopathic generalized versus focal epilepsies. These data indicate that circumscribed epileptogenic lesions can have extended effects on many brain systems. Although epileptic seizures may involve various brain areas, seizure activity does not spread diffusely throughout the brain but propagates along specific anatomic pathways that characterize the underlying epilepsy syndrome. Such a functionally oriented approach may help to better understand a range of clinical phenomena such as the type of cognitive impairment, the development of pharmacoresistance, the propagation pathways of seizures, or the success of epilepsy surgery.

A potential role for substance P and interleukin-6 in the cerebrospinal fluid of Cavalier King Charles Spaniels with neuropathic pain.

BACKGROUND: Neuropathic pain can be a clinical sign in Cavalier King Charles Spaniels (CKCS) with syringomyelia. The pathophysiology of this pain is not fully understood. HYPOTHESIS: Neuropathic pain in CKCS is a result of a neuroinflammatory process. ANIMALS: Twenty-six client-owned dogs: 15 dogs with clinical signs of cervical hyperesthesia (group 1), and 11 dogs without of clinical signs (group 2). METHODS: Dogs were examined by magnetic resonance imaging (MRI). Interleukin-6, tumor necrosis factor alpha, and substance P were measured in CSF and compared with morphological findings on MRI and clinical pain scores. RESULTS: All dogs without clinical signs had symmetrical syringomyelia, whereas in the group with pain, 6 dogs had symmetrical and 9 dogs had asymmetrical syringomyelia. Pain and syringomyelia asymmetry were correlated, and a strong association between pain and dorsal horn involvement of syringomyelia was observed. There was no significant difference between the mean width of the syringomyelia in dogs with or without pain. The concentrations of interleukin-6 and substance P were significantly higher in dogs with neuropathic pain. Tumor necrosis factor alpha was not detected in either group. Concentrations of substance P were significantly higher in dogs with asymmetrical syringomyelia or dorsal horn involvement, whereas interleukin-6 concentrations were not significantly different between groups. CONCLUSION: Release of interleukin-6 and substance P may initiate proinflammatory effects leading to development of persistent pain in CKCSs with syringomyelia.

Localizing seizure-onset zones in presurgical evaluation of drug-resistant epilepsy by electroencephalography/fMRI: effectiveness of alternative thresholding strategies.

BACKGROUND AND PURPOSE: Simultaneous EEG/fMRI is an effective noninvasive tool for identifying and localizing the SOZ in patients with focal epilepsy. In this study, we evaluated different thresholding strategies in EEG/fMRI for the assessment of hemodynamic responses to IEDs in the SOZ of drug-resistant epilepsy. MATERIALS AND METHODS: Sixteen patients with focal epilepsy were examined by using simultaneous 92-channel EEG and BOLD fMRI. The temporal fluctuation of epileptiform signals on the EEG was extracted by independent component analysis to predict the hemodynamic responses to the IEDs. We applied 3 different threshold criteria to detect hemodynamic responses within the SOZ: 1) PA, 2) a fixed threshold at P < .05 corrected for multiple comparison (FWE), and 3) FAV (4000 ± 200 activated voxels within the brain). RESULTS: PA identified the SOZ in 9 of 16 patients; FWE resulted in concordant BOLD signal correlates in 11 of 16, and FAV in 13 of 16 patients. Hemodynamic responses were detected within the resected areas in 5 (PA), 6 (FWE), and 8 (FAV) of 10 patients who remained seizure-free after surgery. CONCLUSIONS: EEG/fMRI is a noninvasive tool for the presurgical work-up of patients with epilepsy, which can be performed during seizure-free periods and is complementary to the ictal electroclinical assessment. Our findings suggest that the effectiveness of EEG/fMRI in delineating the SOZ may be further improved by the additional use of alternative analysis strategies such as FAV.

Fever, sickness behavior, and expression of inflammatory genes in the hypothalamus after systemic and localized subcutaneous stimulation of rats with the Toll-like receptor 7 agonist imiquimod.

The Toll-like receptor 7 (TLR7) agonist imiquimod is used for topical treatment of skin cancers. We studied the consequences of injections of imiquimod into a subcutaneous (s.c.) air pouch or of intraperitoneal (i.p.) injections on the manifestation of fever, sickness behavior, and the peripheral and brain-intrinsic induction of a variety of inflammatory molecules. Rats were given imiqimod s.c. or i.p. (1 or 5 mg/kg). Body temperature, motor activity, and food and water intake were recorded by telemetric devices. Peripheral and brain-intrinsic induction of inflammatory mediators was analyzed by real-time polymerase chain reaction (RT-PCR), bioassays, enzyme-linked immunosorbent assays (ELISAs), and immunohistochemistry. Imiquimod is the first TLR-agonist to produce more potent effects with s.c. than i.p. administration. Peripheral induction of interferons (IFNs) and putative circulating pyrogens corresponded to the magnitude of the illness responses. In the brain, an expression of cytokines (TNFα, IL-1ß, and IL-6) and inducible forms of enzymes for prostaglandin E2 synthesis (COX-2 and mPGES) occurred, which was accompanied by a moderate activation of the transcription factors NFκB and STAT3, and a strong activation of the transcription factor NF-IL6, in cells of specific areas with an open blood-brain barrier. These inflammatory responses noted within the brain were more marked after s.c. administration, than i.p. administration of imiquimod. At a dose of 5 mg/kg, imiquimod causes rather moderate brain-inflammatory responses, which are related to peripheral IFN-expression and possibly mediated by brain-intrinsic activation of NF-IL6 and induction of a proinflammatory cocktail. The lack of a septic-like state in imiquimod-treated rats reinforces the therapeutic use of this drug.

Leptin regulates leukocyte recruitment into the brain following systemic LPS-induced inflammation.

The appetite suppressing hormone leptin has emerged as an important modulator of immune function and is now considered to be a critical link between energy balance and host defense responses to pathogens. These 'adaptive' responses can, in situations of severe and sustained systemic inflammation, lead to adverse effects including brain damage that is partly mediated by neutrophil recruitment into the brain. We examined the contribution of leptin to this process in leptin-deficient (ob/ob), -resistant (db/db) and wild-type (WT) mice injected intraperitoneally with a septic dose of lipopolysaccharide (LPS). This treatment induced a dramatic increase in the number of neutrophils entering the brain of WT mice, an effect that was almost totally abolished in the mutant mice and correlated with a significant reduction in the mRNA levels of interleukin-1beta, intracellular adhesion molecule-1 and neutrophil-specific chemokines. These effects were reversed with leptin replenishment in ob/ob mice leading to recovery of neutrophil recruitment into the brain. Moreover, 48 h food deprivation in WT mice, which decreased circulating leptin levels, attenuated the LPS-induced neutrophil recruitment as did a single injection of an anti-leptin antiserum 4 h before LPS treatment in WT mice. These results provide the first demonstration that leptin has a critical role in leukocyte recruitment to the brain following severe systemic inflammation with possible implications for individuals with altered leptin levels such as during obesity or starvation.

The role of the vagus nerve in mediating the long-term anorectic effects of leptin.

Leptin, the product of the obese (ob) gene, is mainly known for its regulatory role of energy balance by direct activation of hypothalamic receptors. Recently, its function in the acute control of food intake was additionally attributed to activation of the vagus nerve to regulate meal termination. Whether vagal afferent neurones are involved in longer term effects of leptin on food intake, however, remains undetermined. Using vagotomised (VGX) rats, we sought to clarify the contributions of vagal afferents in mediating the long-lasting effect of leptin on appetite suppression. Intraperitoneal (i.p.) injection of leptin (3.5 mg/kg) attenuated food intake at 4, 6, 8 and 24 h and body weight at 24 h postinjection in SHAM-operated rats; however, this response was not abrogated by vagotomy. In a separate study using immunohistochemistry, we observed leptin-induced Fos expression in the nucleus tractus solitarii, a brain structure where vagal afferent fibres terminate. This signal was not attenuated in VGX animals compared to the SHAM group. Moreover, leptin treatment led to a similar level of nuclear STAT3 translocation, a marker of leptin signalling, in the hypothalami of SHAM and VGX animals. In addition to the effects of leptin, vagotomy surgery itself resulted in a decrease of 24 h food intake. Analyses of brains from saline-treated VGX animals revealed a significant induction of Fos in the nucleus tractus solitarii and changes in agouti-related peptide and pro-opiomelanocortin mRNA expression in the hypothalamus compared to their SHAM counterparts, indicating that the vagotomy surgery itself induced a modification of brain activity in areas involved in regulating appetite. Collectively, our data suggest that vagal afferents do not constitute a major route of mediating the regulatory effect of leptin on food intake over a period of several hours.

Antidepressants for the negative symptoms of schizophrenia.

BACKGROUND: Negative symptoms are common in people with schizophrenia and are often difficult to treat with antipsychotic drugs. Treatment often involves the use of various add-on medications such as antidepressants. OBJECTIVES: To review the effects of the combination of antipsychotic and antidepressant drug treatment for management of negative symptoms in schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's register (January 2004). We also contacted authors of included studies in order to identify further trials. SELECTION CRITERIA: We included all randomised controlled trials comparing antipsychotic and antidepressant combinations with antipsychotics alone for the treatment of prominent negative symptoms in schizophrenia and/or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: Working independently, we selected and critically appraised studies, extracted data and analysed on an intention-to-treat basis. Where possible and appropriate we calculated the relative risk RR) and their 95% confidence intervals (CI), with the number needed to treat (NNT). MAIN RESULTS: We included five studies (all short-term, total N=190). We found no significant difference for 'leaving the study early for any reason' between the antipsychotic plus antidepressant combination and the control group (n=90, 3 RCTs, RR 3.0 CI 0.35 to 26.04). Leaving early due to adverse events (n=64, 2 RCTs, RR 5.0 CI 0.26 to 97.0) and leaving the study early due to inefficacy (n=34, 1 RCT, RR 3.0 CI 0.13 to 68.84) also showed no significant difference between the two treatment groups. In terms of clinical response, participants treated with the antipsychotic plus antidepressant medications showed a statistically significant greater improvement (n=30, 1 RCT, WMD -1.0 CI -1.61 to -0.39) and showed a significantly lower severity at endpoint (n=30, 1 RCT, WMD -0.9 CI -1.55 to -0.25) on the Clinical Global Impression Scale than those treated with antipsychotics alone. More people allocated to combination therapy had a clinically significant improvement in negative symptoms compared with those given antipsychotics and placebo (n=60, 2 RCTs, RR 0.56 CI 0.32 to 0.97, NNT 3 CI 3 to 34). Significant differences in favour of the combination therapy were seen in different aspects of negative symptoms: 'affective flattening' (n=30, 1 RCT, WMD -7.0 CI -10.37 to -3.63), 'alogia' (n=26, 1 RCT, WMD -3.00 CI -5.14 to -0.86) and 'avolition' (n=30, 1 RCT, WMD -3.0 CI -5.04 to -0.96). No statistically significant difference was found between treatment groups in regards to the outcome 'at least one adverse event' (n=84, 2 RCTs, RR 1.80 CI 0.66 to 4.90). For movement disorders and other adverse effects, no statistically significant differences were found in any of the studies that provided usable data on these outcomes. There are no data at all on outcomes such as compliance, cost, social and cognitive functioning, relapse, recurrence of negative symptoms, rehospitalisation or quality of life. There are no medium or long term data. AUTHORS' CONCLUSIONS: The combination of antipsychotics and antidepressants may be effective in treating negative symptoms of schizophrenia, but the amount of information is currently too limited to allow any firm conclusions. Large, pragmatic, well-designed and reported long term trials are justified.

Fever and circulating cytokines induced by double-stranded RNA in guinea pigs: dependence on the route of administration and effects of repeated injections.

AIMS: The aim of this study was to characterize the properties of synthetic double-stranded RNA to induce fever and circulating cytokines in guinea pigs with special emphasis on the route of administration and on a putative development of tolerance to this pyrogen. METHODS: Changes in abdominal temperature were recorded in unrestrained animals by use of intra-abdominally implanted radiotransmitters. Circulating concentrations of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured by use of specific bioassays. RESULTS: The pyrogenic effect of double-stranded RNA at a dose of 500 microg kg(-1) depended on the route of its administration. Intra-arterial (i.a.) or intraperitoneal injections of double-stranded RNA induced pronounced fevers and strong elevations of circulating TNF-alpha and IL-6. Intramuscular injections of the synthetic pyrogen caused rather moderate febrile and cytokine responses. Administration of synthetic RNA into artificial subcutaneously implanted Teflon chambers had no pyrogenic and cytokine-inducing effects. I.a. injections of double-stranded RNA, repeated five times at intervals of 3 days, resulted in fevers of similar shape and duration and similar cytokine response patterns. However, the strength of fever and cytokine formation was significantly reduced, although not abolished, in response to the repeated injections compared with the first injection, indicating a partial development of tolerance. CONCLUSIONS: The modulation of the strength of RNA-induced fever, dependent on the route of administration, or the state of partial tolerance to this pyrogen, may thus be related to the formation of pyrogenic cytokines.

[BeKi--an initiative for nutrition education in children: program description and evaluation]. / Landesinitiative BeKi--Bewusste Kinderernährung: Programmbeschreibung und -evaluation.

OBJECTIVES: The State Initiative Be KI is carried out statewide by the Baden-Württemberg Ministry for Nutrition/Food and Rural Area since 1980. Be KI addresses all target groups involved in the upbringing and education of children from age 6 months up to the end of the 6th grade and provides factual, validated, and independent information on child nutrition and nutrition education. Recently a comprehensive evaluation was carried out to assess the public health impact. Program, design and results of the evaluation are presented. METHODS: According to the RE-AIM Model for health promotion programs the evaluation assesses the public health impact in regard of individual and institutional reach, efficacy, adoption, implementation, and maintenance by various methods (e. g. written surveys and interviews with experts of child nutrition, in day care facilities and primary schools supplemented by internal data of the Ministry). RESULTS: Be KI represents the nutrition education program for children in the German language area with the longest uninterrupted operation span. The number of assignments of the child nutrition experts has been increasing ever since Be KI's official inception in 1980. During the school year 2004/2005 the experts carried out 6090 assignments, predominantly in primary schools which accounted for 60% of the assignments. About a third of schools know Be KI. The majority of kindergarten and school teachers who know the experts of child nutrition or the compilation use these offers. Many teachers use Be KI-components without knowing that they belong to Be KI. As a result of Be KI some of the teachers noticed short-time changes: pupils eat healthier break-time snacks and change their attitude towards a more balanced diet. Concerning the frequency of nutrition education and teachers attitude there are hardly any differences between institutions with Be KI and without Be KI. CONCLUSION: Be KI meets the main requirements of effective nutrition education programs for children: it is creative, engaging, inexpensive an widely dissiminated. Contents and methods of the provided materials correspond to the development level of the target groups. But communication and networking with educational institutions as well as public relations should be intensified and teachers in day care facilities and school teachers should be motivated to work with the Be KI-materials on their own (empowerment). Room for improvement exists in regard of a permanent straightforward evaluation system and a more pronounced orientation of the prevention program towards the social environment would be helpful.

[A telephone hotline as an easily accessible service for questions on schizophrenia]. / Telefon-Hotline als niederschwelliges Angebot für Fragen zur Schizophrenie.

Public relations activities of the German Research Network on Schizophrenia (GRNS) have shown that there is a demand for more information about schizophrenia disorder. This confirms international research findings that relatives of schizophrenia patients are particularly in need of information and support. In response, the GRNS has maintained a telephone hotline since 2001. The hotline is manned by clinical experts, psychiatrists, or psychologists once a week. The telephone calls are documented in a systematic manner. From 2001 to 2003, 3,909 calls were registered. This volume exceeds the limit of the hotline's resources. The telephone hotline is mainly used by relatives of psychotic patients. Most questions relate to the symptoms of schizophrenia and pharmaceutical treatment. The need for emotional support is also a high motivational factor for dialing the hotline number. The telephone hotline seems to be a worthwhile addition to the already existing crisis telephones and should be maintained even after public funding of the network expires.

European psychiatric treatment guidelines: is the glass half full or half empty?

PURPOSE: We assessed the quality of European treatment guidelines in the field of mental health that have been produced by national psychiatric associations. The main focus was the question of whether the development process of the guidelines followed basic principles of evidence-based medicine. METHODS: Sixty-one European clinical practice guidelines from 14 countries, published between 1998 and 2003, were assessed using the 'Appraisal of Guidelines for Research and Evaluation (AGREE) Instrument'. The domain score was calculated for each of the six domains of the AGREE instrument. The seven items of the domain "rigor of development" and one additional item concerning national particularities were assessed in detail. RESULTS: The mean scores in the six domains were rather low, although the quality varied among the different guidelines. The highest mean score was obtained in the domain clarity and presentation (70.8% S.D. 23.5), the lowest on editorial independence (19.7% S.D. 29.3). The recommendations of about half of the assessed guidelines could be considered to be evidence-based. CONCLUSION: The assessed guidelines showed a broad range of quality: some producers attached importance to an evidence-based development process; but in spite of this, a large number of guidelines were only of middling quality. As national particularities are only rarely mentioned and the development process of guidelines is complex, an international collaboration that aims toward the production of shareable guidelines might be promising.