iMPI: portable human-sized magnetic particle imaging scanner for real-time endovascular interventions.

Minimally invasive endovascular interventions have become an important tool for the treatment of cardiovascular diseases such as ischemic heart disease, peripheral artery disease, and stroke. X-ray fluoroscopy and digital subtraction angiography are used to precisely guide these procedures, but they are associated with radiation exposure for patients and clinical staff. Magnetic Particle Imaging (MPI) is an emerging imaging technology using time-varying magnetic fields combined with magnetic nanoparticle tracers for fast and highly sensitive imaging. In recent years, basic experiments have shown that MPI has great potential for cardiovascular applications. However, commercially available MPI scanners were too large and expensive and had a small field of view (FOV) designed for rodents, which limited further translational research. The first human-sized MPI scanner designed specifically for brain imaging showed promising results but had limitations in gradient strength, acquisition time and portability. Here, we present a portable interventional MPI (iMPI) system dedicated for real-time endovascular interventions free of ionizing radiation. It uses a novel field generator approach with a very large FOV and an application-oriented open design enabling hybrid approaches with conventional X-ray-based angiography. The feasibility of a real-time iMPI-guided percutaneous transluminal angioplasty (PTA) is shown in a realistic dynamic human-sized leg model.

[Borderline personality disorder: state of knowledge and attitudes among french-speaking mental health professionnals]. / Trouble de la personnalité borderline: état des connaissances et des représentations auprès de praticiens francophones en santé mentale.

OBJECTIVES: Patients suffering from borderline personality disorder are very prevalent in various settings (emergency rooms, psychiatric and general hospitals, ambulatory consultations). However, it remains one of the most stigmatized and neglected mental health conditions, albeit being an area that is responsible for very interesting advances in psychotherapy. Today, the prognosis of patients with borderline personality disorder is rather favorable, provided that they follow a dedicated psychotherapy. Conceptions about this condition therefore deserve to be updated as it is sufficiently described in the literature that negative attitudes towards these patients diminish the quality of care they receive as well as their prognosis, and that these attitudes change with training. We decided to study the state of knowledge and attitudes towards borderline personality disorder in a group of French-speaking caregivers interested in these patients. METHODS: Between 2019 and 2020, at the start of training sessions in psychotherapeutic approaches to borderline personality disorder, we provided two questionnaires to 126 caregivers from various professional backgrounds (psychiatrists or child psychiatrists, psychologists, mental health nurses, social workers). The first consisted of 13 questions with 3 choice answers aimed at testing knowledge about borderline personality disorder and the second of 11 questions in the form of a Likert scale aimed at evaluating attitudes towards these patients (e.g. degree of comfort, involvement, hope, avoidance with these patients) adapted frome a questionnaire of Blake and colleagues. RESULTS: The sample consisted of 126 caregivers (69 psychiatrists/pedopsychiatrists; 19 mental health nurses; 23 psychologists; 14 social workers). Fifty three of them (42.06 %) worked in an outpatient setting (either in a state facility or in private practice), 50 (39.68 %) worked in an inpatient psychiatric unit, 13 (10.32%) in both care systems, and 10 (7.94 %) worked in other facilities such as sheltered homes or workshops for persons with psychiatric disabilities. The average number of years in postgraduate training was 7.73 (SD=5.67; rank=0 to 31), and 35 (27.78%) had received at least one training course on borderline disorder in the past. The mean age of the sample was 37.89 (SD=10.08; rank=20 to 64) and there were 76 women (60.32%) and 50 men (39.68%). Concerning the first questionnaire (knowledge), the rate of correct responses among caregivers was relatively low (54%) considering that the vast majority of those assessed were caregivers already trained in mental health who were working with patients suffering from borderline personality disorder. The results showed a significant knowledge gap among professionals, in particular in the nursing profession, illustrating an ever more flagrant shortfall in formations in this sub-population. Concerning the second questionnaire (attitudes), the answers showed that attitudes of caregivers towards patients with borderline personality disorder were still tinged with fear and lack of confidence in taking charge of them. Thus, one participant out of five would have liked to avoid these patients, more than 12% of caregivers did not appreciate them, and 23% thought that they were manipulative. In addition, nearly half of the caregivers surveyed had low confidence in their ability to make a positive difference in the lives of borderline patients. However, there was a recognition of their distress as well as a demand for dedicated training. CONCLUSIONS: Stigmas and ignorance persist around patients with borderline personality disorder. Current training courses do not allow caregivers who are on the front lines (in particular nurses) and who wish to be trained to acquire sufficient knowledge and tools necessary for the care of patients suffering from this disorder. This calls for an improvement in training as well as a reflection on the most appropriate approaches possible to the various target audiences.

Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants.

Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug.Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

Normal Load and Counter Body Size Influence the Initiation of Microstructural Discontinuities in Copper during Sliding.

Near the interface of two contacting metallic bodies in relative motion, the microstructure changes. This modified microstructure leads to changes in material properties and thereby influences the tribological behavior of the entire contact. Tribological properties such as the friction coefficient and wear rate are controlled by the microstructure, while the elementary mechanisms for microstructural changes are not sufficiently understood. In this paper, the influence of the normal load and the size of the counter body on the initiation of a tribologically induced microstructure in copper after a single sliding pass is revealed. A systematic variation in the normal load and sphere diameter resulted in maximum Hertzian contact pressures between 530 MPa and 1953 MPa. Scanning electron microscopy, focused ion beam, and transmission electron microscopy were used to probe the subsurface deformation. Irrespective of the normal load and the sphere diameter, a sharp line-like feature consisting of dislocations, the so-called dislocation trace line, was identified in the subsurface area at depths between 100 nm and 400 nm. For normal loads below 6.75 N, dislocation features are formed below this line. For higher normal loads, the microstructure evolution directly underneath the surface is mainly confined to the area between the sample surface and the dislocation trace line, which itself is located at increasing depth. Transmission Kikuchi diffraction and transmission electron microscopy demonstrate that the misorientation is predominantly concentrated at the dislocation trace line. The results disclose a material rotation around axes roughly parallel to the transverse direction. This study demonstrates the generality of the trace line phenomena over a wide range of loads and contact pressures and the complexity of subsurface processes under a sliding contact and provides the basis for modeling the early stages in the microstructure evolution.

Emergency psychiatric management of borderline personality disorder: Towards an articulation of modalities for personalised integrative care.

Building on existing literature, the authors draw the landscape of psychiatric emergencies, and focus on borderline personality disorder, frequently encountered, and strongly linked to death by suicide. A review of knowledge in terms of diagnosis, prognosis, etiology, and treatment, as well as their own experiences, lead them to propose areas of progress that would secure the patient's care pathway. The evolution of society has led psychiatric emergency departments to play the role of a safety net and an entry point to the mental health system. Borderline personality disorder is one of the most common pathologies encountered in psychiatric emergencies. It represents a major concern, long characterized by an often dramatic evolution, and by the human and economic stress it generates. However, since the 1990s, knowledge of this disorder has been refined, and today there are various means of evaluation, good clinical practices and psychotherapeutic treatments, thanks to which significant and lasting improvement is possible. Recent studies highlight the crucial role of hospital caregivers, and the benefit of consolidating their skills by providing them with the knowledge and tools specific to this disorder. They also converge on the interest of setting up specific emergency treatment modalities, particularly highly structured, safe and empowering for the patient, in order to improve their effectiveness. The authors suggest that a case formulation model for persons with borderline personality disorder in emergency would make it possible to activate these two levers of progress, while improving collaboration between hospital and outpatient care. This would also address their main concern of optimizing the patient's therapeutic pathway and reinforcing adherence to treatment that could bring remission, and should be supported by data from empirical research.

Early deformation mechanisms in the shear affected region underneath a copper sliding contact.

Dislocation mediated plastic deformation decisively influences the friction coefficient and the microstructural changes at many metal sliding interfaces during tribological loading. This work explores the initiation of a tribologically induced microstructure in the vicinity of a copper twin boundary. Two distinct horizontal dislocation traces lines (DTL) are observed in their interaction with the twin boundary beneath the sliding interface. DTL formation seems unaffected by the presence of the twin boundary but the twin boundary acts as an indicator of the occurring deformation mechanisms. Three concurrent elementary processes can be identified: simple shear of the subsurface area in sliding direction, localized shear at the primary DTL and crystal rotation in the layers above and between the DTLs around axes parallel to the transverse direction. Crystal orientation analysis demonstrates a strong compatibility of these proposed processes. Quantitatively separating these different deformation mechanisms is crucial for future predictive modeling of tribological contacts.

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

Violence exposure and resulting psychological effects suffered by psychiatric visiting nurses in Japan.

WHAT IS KNOWN ON THE SUBJECT?: There is a developing body of research on violence in healthcare workplaces. Although psychiatric visiting nurses (PVNs) are an important group of professionals who provide medical services for people with mental disorders live in the community, little is known about the experiences and characteristics of violence exposure among PVNs, or the characteristics and work situations of PVNs related to violence exposure. WHAT THIS STUDY ADDS TO EXISTING KNOWLEDGE?: Approximately 40% of participants were exposed to violence during the previous 12 months; approximately 50% had been exposed during their PVN careers in PVN settings. The most frequent violence was verbal abuse. Longer career length as a PVN and greater number of visits per month were both positively associated with verbal abuse during the previous 12 months. Twenty-eight of the 34 participants (83%) who completed the IES-R-J survey had some residual psychological distress, and two (6%) had a potentially high risk of posttraumatic stress disorder. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: In devising policies and strategies against violence, PVN organizations and administrators should consider the characteristics of the violence, especially verbal abuse, as well as the characteristics and work situations of PVNs that are related to verbal abuse. Furthermore, they might provide relevant information on violence in PVN settings within their violence-prevention manuals or education. It would be important to provide support and to construct a safe workplace environment for PVNs who are experiencing residual psychological distress. ABSTRACT: Introduction Psychiatric visiting nurses (PVNs) play a crucial role by providing medical services for community-living individuals with mental disorders in Japan. However, little is known about violence towards PVNs. Aim This cross-sectional study investigated violence during visits and the resulting psychological effects for PVNs. Methods PVNs were assessed using a violence exposure questionnaire and the Impact of Event Scale-Revised (IES-R-J); a measure of posttraumatic distress. Result Thirty-eight (41%) of 94 participants had experienced violence during the previous 12 months and 49 (53%) over their entire career. The most frequent violence was verbal abuse. Career length as a PVN and number of visits per month were significantly positively associated with verbal abuse during the previous 12 months. The IES-R-J scores indicated 28 of the 34 participants who completed the questionnaire exhibited psychological distress for the most traumatic violence during their career and two had a potentially high risk of posttraumatic stress disorder. Discussion and Implications Policies and strategies aimed at reducing violence in PVN settings should be developed according to characteristics of the violence, as well as the characteristics and work situation of PVNs. Furthermore, the provision of support and a safe workplace environment would be important for PVNs with residual psychological distress.

Conflicts, security and marginalisation: institutional change of the pastoral commons in a 'glocal' world.

This paper argues that pastoral commons are under increasing pressure not just from overuse by pastoralists themselves, but from land management policies. Since colonial times, these have been based on a persistent misconception of the nature of pastoral economies and combined with increasing land alienation and fragmentation through government policies and covert privatisation of pastures. The paper focuses especially on pastoral populations in African drylands and is based on long-term research by independent researchers summarising some of their experiences in western, eastern and southern Africa. Most of them are organised in the African Drylands Dialogue, trying to shed some light on the developments in these areas. Before discussing the actual situation of African pastoralists, the authors focus on basic institutional features of the political and economic management of common grazing lands. This is followed by an overview of land alienation processes in colonial times, which serves as a basis for understanding the current land alienation constellations. The paper then moves on to explain how and why pastoralists are framed by the national discourses as the 'other' and the 'troublemaker', even being labelled as terrorists in nation state contexts. This goes hand in hand with a new wave of land alienation in the form of large-scale land acquisitions or 'land grabbing' (including water grabbing and 'green grabbing' processes). The paper then outlines different coping and adaptation strategies adopted by pastoral groups in a context in which a range of different global and local political, economic and ecological situations interrelate ('glocal'). Finally, the paper discusses the way in which pastoralism could be reframed in a participatory way in the future.

Les auteurs de cet article soutiennent que la pression foncière croissante exercée sur les terres collectives pastorales n'est pas seulement imputable à la surexploitation par les pasteurs eux-mêmes mais résulte surtout des politiques de gestion des terres. Depuis le temps des colonies, ces politiques ont reposé sur une perception erronée et tenace de la nature même des économies pastorales, à laquelle se sont greffées l'aliénation croissante des terres et leur fragmentation impulsée par les politiques gouvernementales et par la privatisation dissimulée des prairies. Les auteurs s'intéressent particulièrement aux populations pastorales des régions arides d'Afrique et exposent les conclusions d'une étude conduite sur une longue durée par une équipe indépendante de chercheurs, résumant l'essentiel de leurs observations en Afrique de l'Ouest, de l'Est et australe. La plupart d'entre eux oeuvrent sous les auspices d'African Drylands Dialogue et tentent de faire la lumière sur les évolutions constatées dans ces régions. Avant de se pencher sur la situation des pasteurs africains aujourd'hui, les auteurs décrivent les principales caractéristiques institutionnelles de la gestion politique et économique des terres collectives dédiées au pâturage. Ils retracent ensuite les processus d'aliénation des terres opérés durant l'époque coloniale, qui servent de grille de lecture pour mieux comprendre les constellations actuelles de terres aliénées. Puis les auteurs expliquent comment et pourquoi les discours nationaux désignent les pasteurs comme « l'autre ¼ et le « fauteur de troubles ¼, quand ils ne les dépeignent pas comme des terroristes dans les contextes d'étatsnations. Ces accusations sont indissociables d'une nouvelle vague d'aliénation des terres, qui prend la forme d'acquisitions à grande échelle ou de réquisitions (y compris les processus d'appropriation des cours d'eau ou d'écosystèmes [green grabbing]). Les auteurs détaillent les stratégies mises en oeuvre par les groupes pastoraux pour faire face à cette évolution et s'y adapter, dans un contexte de forte interaction entre de nombreuses situations politiques, économiques et écologiques de portée tant mondiale que locale (niveau dit « glocal ¼). Enfin, les auteurs examinent les perspectives d'avenir du pastoralisme à travers un nouveau cadre de type participatif.

Los autores postulan que el patrimonio pastoral común se encuentra sometido a presiones crecientes, no solo a resultas de su explotación excesiva por parte de los propios pastores, sino también a consecuencia de las políticas de ordenación del territorio. Desde los tiempos coloniales, estas se basan en un equívoco pertinaz acerca del carácter de las economías pastorales, a lo que se suma un nivel creciente de enajenación y fragmentación de las tierras a resultas de las políticas públicas y la privatización encubierta de los pastos. Los autores prestan especial atención a las poblaciones pastorales de las tierras áridas africanas, basándose en investigaciones de larga duración realizadas por investigadores independientes y resumiendo parte de su experiencia en el África occidental, oriental y meridional. La mayoría de ellos están adscritos al African Drylands Dialogue [diálogo sobre las tierras áridas africanas] y tratan por esta vía de arrojar luz sobre la evolución de esas zonas. Antes de presentar la situación real de las sociedades de pastores africanas, los autores se detienen en una serie de rasgos institucionales básicos de la gestión política y económica de los pastizales de propiedad común. A continuación exponen a grandes líneas los procesos de enajenación de las tierras en la época colonial, que encierran elementos básicos para comprender la actual constelación de tierras enajenadas. Después pasan a explicar cómo y por qué en el discurso de ciertos países las sociedades de pastores han acabado representando la alteridad, percibida además como «agitadora¼, hasta llegar a ser etiquetadas de «terroristas¼ en algunos estados-nación, paralelamente a una nueva oleada de enajenación de tierras en forma de adquisiciones a gran escala o «acaparamiento de tierras¼ (lo que incluye procesos de acaparamiento del agua y «acaparamiento ecológico¼). Tras exponer diferentes estrategias de respuesta y adaptación adoptadas por los grupos pastorales en un contexto marcado por la imbricación entre diversas realidades políticas, económicas y ecológicas («glocal¼), los autores concluyen reflexionando sobre el modo en que en el futuro sería posible reestructurar el pastoreo pasando por métodos participativos.

A reciprocating optical in situ tribometer with high-speed data acquisition.

Tribology is the science of interacting surfaces in relative motion. Processes like the transition from static to dynamic friction are fast and complex, especially as the contacting interface is buried. A direct view at the interface, in order to gain a deeper understanding of the interaction between the materials, is therefore of great interest. The reciprocating optical in situ tribometer introduced here observes the interface of two contacting materials (one of them being optical transparent) with a high-speed camera, taking up to 230 000 frames per second. The camera is attached to an optical microscope with a magnification of up to 2500 times. Friction forces are measured by an analog laser detection setup, with a maximum sampling rate of 500 kHz. The sliding motion of the materials is realized by two displacement units. A linear positioning stage allows velocities between 500 nm/s and 100 mm/s for a maximum distance of 200 mm. For smaller velocities, and to exclude breakaway torque, a piezo actuator can be used. The maximum displacement distance of the piezo actuator is 120 µm. The smallest applicable normal load on the samples is 0.5 N which is applied by the dead weights. Tribological experiments to investigate the transition from static to dynamic friction have been performed with morphologically textured brass hemispheres in contact with the sapphire discs. Sapphire was chosen for its high hardness and optical transparency. These experiments revealed, due to the high data acquisition possible with the new setup, a so far unobserved effect during the transition from static to dynamic friction.

Extraction of shear viscosity in stationary states of relativistic particle systems.

Starting from a classical picture of shear viscosity we construct a stationary velocity gradient in a microscopic parton cascade. Employing the Navier-Stokes ansatz we extract the shear viscosity coefficient η. For elastic isotropic scatterings we find an excellent agreement with the analytic values. This confirms the applicability of this method. Furthermore, for both elastic and inelastic scatterings with pQCD based cross sections we extract the shear viscosity coefficient η for a pure gluonic system and find a good agreement with already published calculations.

The effect of age, sex, smoking and co-medication on serum levels of venlafaxine and O-desmethylvenlafaxine under naturalistic conditions.

INTRODUCTION: Venlafaxine (VEN) is a modern antidepressant which exerts both serotonin and norepinephrine reuptake inhibition. In this study we examined the influence of age, sex, smoking, and co-medication on serum levels of VEN and its metabolite O-desmethylvenlafaxine (ODVEN) in patients treated with VEN under naturalistic conditions. METHODS: We retrospectively evaluated 478 TDM analyses of VEN requested in the Pychiatric University Hospitals of Mainz, Regensburg, and Würzburg. The determination of serum levels was performed by virtually identical chromatographic methods in the TDM laboratories of the participating hospitals. RESULTS: Serum levels varied widely on each dose level. Women had about 30% higher dose-corrected serum levels of VEN and ODVEN than men (p<0.01), and patients older than 60 years showed about 46% higher levels of both compounds than younger ones (p<0.01). In smokers, mean serum levels of ODVEN were 21% lower than in non-smokers. Combining these variables a considerable increase of the differences between the subgroups was found indicating an additive effect. ANOVA over the 8 different groups was significant for ODVEN (p<0.01) and sum (p<0.01), but not for VEN (n.s.). Co-medication with other psychotropic drugs was associated with a decreasing ODVEN/VEN ratio indicating a reduced metabolism in patients receiving polypharmacy. DISCUSSION: These findings show that TDM is useful to identify factors affecting the pharmacokinetic properties of VEN. It is concluded that sex, age and smoking should be considered for optimal dosing of patients with VEN.

Biochemical markers of bone turnover during pregnancy in horses: a longitudinal study.

The effect of pregnancy on bone metabolism was investigated in healthy mares. Venous blood samples were collected 7 times from 19 multiparous mares starting at 20-weeks pre-parturition, continuing 6 times in 4-week intervals, including the week of parturition and one week after parturition. Serum concentrations of osteocalcin (OC) and carboxy-terminal cross-linking telopeptide of type I collagen (CTX-I) were determined. Measurement cycles and age had a significant (p < 0.01) influence on OC and CTX-I values. Pregnancy influenced bone metabolism with peak bone formation and resorption values around the time of parturition.

AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint eff ort.

AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate- and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint effort.

Closed traumatic brain injury model in sheep mimicking high-velocity, closed head trauma in humans.

To date, there are only a few, non-evidence based, cerebroprotective therapeutic strategies for treatment and, accordingly, for prevention of secondary brain injuries following severe closed head trauma. In order to develop new therapy strategies, existing realistic animal models need to be advanced. The objective is to bridge standardized small animal models and actual patient medical care, since the results of experimental small animal studies often cannot be transferred to brain-injured humans. For improved standardization of high-velocity trauma, new trauma devices for initiating closed traumatic brain injury in sheep were developed. The following new devices were tested: 1. An anatomically shaped rubber bolt with an integrated oscillation absorber for prevention of skull fractures; 2. Stationary mounting of the bolt to guarantee stable experimental conditions; 3. Varying degrees of trauma severity, i. e., mild and severe closed traumatic brain injury, using different cartridges; and 4. Trauma analysis via high-speed video recording. Peritraumatic measurements of intracranial pressure, brain tissue pH, brain tissue oxygen, and carbon dioxide pressure, as well as neurotransmitter concentrations were performed. Cerebral injuries were documented with magnetic resonance imaging and compared to neuropathological results. Due to the new trauma devices, skull fractures were prevented. The high-speed video recording documented a realistic trauma mechanism for a car accident. Enhancement of extracellular glutamate, aspartate, and gamma amino butyric acid concentrations began 60 min after the trauma. Magnetic resonance imaging and neuropathological results showed characteristic injury patterns of mild, and severe, closed traumatic brain injury. The severe, closed traumatic brain injury group showed diffuse axonal injuries, traumatic subarachnoid hemorrhage, and hemorrhagic contusions with inconsistent distribution among the animals. The model presented here achieves a gain in standardization of severe, closed traumatic brain injury by increasing approximation to reality. The still existent heterogeneity of brain pathology mimics brain changes observed in patients after high-energy trauma. This model seems to close the gap between experimental small animal models and clinical studies. However, further investigations are needed to evaluate if this model can be used for testing new therapeutic strategies for these patients.

2-(4-(Biphenyl-4-ylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (HZ52)--a novel type of 5-lipoxygenase inhibitor with favourable molecular pharmacology and efficacy in vivo.

BACKGROUND AND PURPOSE: 5-Lipoxygenase (5-LO) is the key enzyme in the biosynthesis of pro-inflammatory leukotrienes (LTs) representing a potential target for pharmacological intervention with inflammation and allergic disorders. Although many LT synthesis inhibitors are effective in simple in vitro test systems, they frequently fail in vivo due to lack of efficacy. Here, we attempted to assess the pharmacological potential of the previously identified 5-LO inhibitor 2-(4-(biphenyl-4-ylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (HZ52). EXPERIMENTAL APPROACH: We evaluated the efficacy of HZ52 in vivo using carrageenan-induced pleurisy in rats and platelet-activating factor (PAF)-induced lethal shock in mice. We also characterized 5-LO inhibition by HZ52 at the cellular and molecular level in comparison with other types of 5-LO inhibitor, that is, BWA4C, ZM230487 and hyperforin. KEY RESULTS: HZ52, 1.5 mg·kg⁻¹ i.p., prevented carrageenan-induced pleurisy accompanied by reduced LTB(4) levels and protected mice (10 mg·kg⁻¹, i.p.) against PAF-induced shock. Detailed analysis in cell-based and cell-free assays revealed that inhibition of 5-LO by HZ52 (i) does not depend on radical scavenging properties and is reversible; (ii) is not impaired by an increased peroxide tone or by elevated substrate concentrations; and (iii) is little affected by the cell stimulus or by phospholipids, glycerides, membranes or Ca²âº. CONCLUSIONS AND IMPLICATIONS: HZ52 is a promising new type of 5-LO inhibitor with efficacy in vivo and with a favourable pharmacological profile. It possesses a unique 5-LO inhibitory mechanism different from classical 5-LO inhibitors and seemingly lacks the typical disadvantages of former classes of LT synthesis blockers.

Predicting PBSC harvest failure using circulating CD34 levels: developing target-based cutoff points for early intervention.

PBSCs are usually mobilized using G-CSF with or without chemotherapy. With the emergence of newer mobilizing agents, predicting poor mobilization may allow early intervention and prevent the costs and complications associated with remobilization. We retrospectively evaluated a cohort of 1556 patients seen between January 2000 and September 2008 with multiple myeloma (565; 36%), non-Hodgkin's lymphoma (NHL) (562; 36%), amyloidosis (345; 22%) or Hodgkin's disease (94; 6%), who were initially mobilized with single agent G-CSF. Sensitivity and specificity analysis was used to identify ideal peripheral blood CD34 count (PB-CD34) cutoff points that predicted successful collection. In patients with plasma cell disorders, a PB-CD34 count of 11, 17, 21 and 28/µL by day 4 or 5 was required to collect a target of 2, 4, 8 or 12 million cells/kg, respectively. A CD34 yield of <0.8 million cells/kg on first apheresis also predicted for <2 million CD34 cells/kg. For patients with NHL or Hodgkin's disease, a PB-CD34 count of <6 and <15/µL on day 4 or 5 predicted failure to achieve a target collection of 2 and 4 million cells/kg, respectively. This study suggests that PB-CD34 thresholds should be based on collection target to allow for early intervention and to prevent collection failures.

Remote switching of temperature, gaseous, and aqueous phase in a low-volume interface chamber for brain slices.

A new remote-controlled interface-type chamber was designed in order to conduct experiments in brain slices involving gas, fluid, and temperature changes with as little tissue manipulation as possible. The chamber allows for extremely quick changes between different fluid and/or gaseous phases and for active cooling as well as heating by using a set of electromechanical valves and Peltier elements. The design drawings are complemented by exemplary tests of temperature and gas changes, and electrophysiological recordings of slices manipulated with gas and fluid alterations were used to test the efficacy and accuracy of the design. Changing between normoxia and anoxia needs less than 30 s, while the readjustment of the chamber to a new, preset temperature is accomplished in about 1 min. Supplementary data provide a proposal for the electronic circuit diagram. This chamber design should simplify data acquisition in interface environments.