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Background: Malignant ascites commonly occurs in advanced or recurrent stages of epithelial ovarian cancer during peritoneal carcinomatosis and is correlated with poor prognosis. Due to its complex composition of cellular and acellular components malignant ascites creates a unique tumor microenvironment, which mediates immunosuppression and promotes progression of disease. However, the immunosuppressive mechanisms remain poorly understood. Methods: In the present study, we explored the antitumor activity of healthy donor NK and T cells directed against ovarian cancer cells in presence of malignant ascites derived from patients with advanced or recurrent peritoneal carcinomatosis. A wide range of methods was used to study the effect of ascites on NK and T cells (FACS, ELISA, EliSpot, qPCR, Live-cell and confocal microscopy, Western blot and electrolyte flux assays). The ascites components were assessed using quantitative analysis (nephelometry, potentiometry and clinical chemistry) and separation methods (dialysis, ultracentrifugal filtration and lipid depletion). Results: Ascites rapidly inhibited NK cell degranulation, tumor lysis, cytokine secretion and calcium signaling. Similarly, target independent NK and T cell activation was impaired in ascites environment. We identified imbalanced electrolytes in ascites as crucial factors causing extensive immunosuppression of NK and T cells. Specifically, high sodium, low chloride and low potassium content significantly suppressed NK-mediated cytotoxicity. Electrolyte imbalance led to changes in transcription and protein expression of electrolyte channels and impaired NK and T cell activation. Selected inhibitors of sodium electrolyte channels restored intracellular calcium flux, conjugation, degranulation and transcript expression of signaling molecules. The levels of ascites-mediated immunosuppression and sodium/chloride/potassium imbalance correlated with poor patient outcome and selected molecular alterations were confirmed in immune cells from ovarian cancer patients. Conclusion: Our data suggest a novel electrolyte-based mechanism of immunosuppression in malignant ascites of patients with peritoneal carcinomatosis. We show for the first time that the immunosuppression of NK cytotoxicity in coculture assays is correlated to patient poor survival. Therapeutic application of sodium channel inhibitors may provide new means for restoring immune cell activity in ascites or similar electrolyte imbalanced environments. [ABSTRACT FROM AUTHOR]

Background: Malignant ascites commonly occurs in advanced or recurrent stages of epithelial ovarian cancer during peritoneal carcinomatosis and is correlated with poor prognosis. Due to its complex composition of cellular and acellular components malignant ascites creates a unique tumor microenvironment, which mediates immunosuppression and promotes progression of disease. However, the immunosuppressive mechanisms remain poorly understood. Methods: In the present study, we explored the antitumor activity of healthy donor NK and T cells directed against ovarian cancer cells in presence of malignant ascites derived from patients with advanced or recurrent peritoneal carcinomatosis. A wide range of methods was used to study the effect of ascites on NK and T cells (FACS, ELISA, EliSpot, qPCR, Live-cell and confocal microscopy, Western blot and electrolyte flux assays). The ascites components were assessed using quantitative analysis (nephelometry, potentiometry and clinical chemistry) and separation methods (dialysis, ultracentrifugal filtration and lipid depletion). Results: Ascites rapidly inhibited NK cell degranulation, tumor lysis, cytokine secretion and calcium signaling. Similarly, target independent NK and T cell activation was impaired in ascites environment. We identified imbalanced electrolytes in ascites as crucial factors causing extensive immunosuppression of NK and T cells. Specifically, high sodium, low chloride and low potassium content significantly suppressed NK-mediated cytotoxicity. Electrolyte imbalance led to changes in transcription and protein expression of electrolyte channels and impaired NK and T cell activation. Selected inhibitors of sodium electrolyte channels restored intracellular calcium flux, conjugation, degranulation and transcript expression of signaling molecules. The levels of ascites-mediated immunosuppression and sodium/chloride/potassium imbalance correlated with poor patient outcome and selected molecular alterations were confirmed in immune cells from ovarian cancer patients. Conclusion: Our data suggest a novel electrolyte-based mechanism of immunosuppression in malignant ascites of patients with peritoneal carcinomatosis. We show for the first time that the immunosuppression of NK cytotoxicity in coculture assays is correlated to patient poor survival. Therapeutic application of sodium channel inhibitors may provide new means for restoring immune cell activity in ascites or similar electrolyte imbalanced environments. [ABSTRACT FROM AUTHOR]

This paper presents an immersed, isogeometric finite element framework to predict the response of multi-material, multi-physics problems with complex geometries using locally refined discretizations. To circumvent the need to generate conformal meshes, this work uses an extended finite element method (XFEM) to discretize the governing equations on non-conforming, embedding meshes. A flexible approach to create truncated hierarchical B-splines discretizations is presented. This approach enables the refinement of each state variable field individually to meet field-specific accuracy requirements. To obtain an immersed geometry representation that is consistent across all hierarchically refined B-spline discretizations, the geometry is immersed into a single mesh, the XFEM background mesh, which is constructed from the union of all hierarchical B-spline meshes. An extraction operator is introduced to represent the truncated hierarchical B-spline bases in terms of Lagrange shape functions on the XFEM background mesh without loss of accuracy. The truncated hierarchical B-spline bases are enriched using a generalized Heaviside enrichment strategy to accommodate small geometric features and multi-material problems. The governing equations are augmented by a formulation of the face-oriented ghost stabilization enhanced for locally refined B-spline bases. We present examples for two- and three-dimensional linear elastic and thermo-elastic problems. The numerical results validate the accuracy of our framework. The results also demonstrate the applicability of the proposed framework to large, geometrically complex problems. [ABSTRACT FROM AUTHOR]

Purpose: Hyperreflective foci are poorly understood transient elements seen on optical coherence tomography (OCT) of the retina in both healthy and diseased eyes. Systematic studies may benefit from the development of automated tools that can map and track such foci. The outer nuclear layer (ONL) of the retina is an attractive layer in which to study hyperreflective foci as it has no fixed hyperreflective elements in healthy eyes. In this study, we intended to evaluate whether automated image analysis can identify, quantify and visualize hyperreflective foci in the ONL of the retina. Methods: This longitudinal exploratory study investigated 14 eyes of seven patients including six patients with optic neuropathy and one with mild non‐proliferative diabetic retinopathy. In total, 2596 OCT B‐scan were obtained. An image analysis blob detector algorithm was used to detect candidate foci, and a convolutional neural network (CNN) trained on a manually labelled subset of data was then used to select those candidate foci in the ONL that fitted the characteristics of the reference foci best. Results: In the manually labelled data set, the blob detector found 2548 candidate foci, correctly detecting 350 (89%) out of 391 manually labelled reference foci. The accuracy of CNN classifier was assessed by manually splitting the 2548 candidate foci into a training and validation set. On the validation set, the classifier obtained an accuracy of 96.3%, a sensitivity of 88.4% and a specificity of 97.5% (AUC 0.989). Conclusion: This study demonstrated that automated image analysis and machine learning methods can be used to successfully identify, quantify and visualize hyperreflective foci in the ONL of the retina on OCT scans. [ABSTRACT FROM AUTHOR]

One feature of papillary thyroid cancer (PTC) is the frequently present somatic BRAFV600E mutation. PTCs are also characterized by a lymphocytic infiltration, which may correlate with an improved clinical outcome. The objective of the study was the characterization of BRAFV600E specific anti-immunity in PTC patients and correlation analyses with the clinical outcome. Fourteen HLA A2 positive PTC patients were included into the study of whom tumor tissue samples were also available. Of those, 8 PTC patients revealed a somatic BRAFV600E mutation. All PTC patients were also MHC class II typed. Tetramer analyses for detection of MHC class I and MHC class II-restricted, BRAFV600E epitope-specific T cells using unstimulated and peptide-stimulated T cells were performed; correlation analyses between MHC phenotypes, T cell immunity, and the clinical course were performed. In regard to unstimulated T cells, a significantly higher amount of BRAFV600E epitope specific T cells was detected compared to a control tetramer. Importantly, after overnight peptide stimulation a significantly higher number of BRAFV600E positive and BRAF WT epitope-specific T cells could be seen. In regard to the clinical course, however, no significant differences were seen, neither in the context of the initial tumor size, nor in the context of lymph node metastases or peripheral metastastic spread. In conclusion, we clearly demonstrated a BRAF-specific tumor immunity in PTC-patients which is, however, independent of a BRAFV600E status of the PTC patients. [ABSTRACT FROM AUTHOR]

Beyond this, it is even unclear how "normative" developmental experiences contribute to stress-related behaviours (Farber et al., 2020), but it may be that broader environmental factors, such as access to green space, may contribute to resilience and reduced stress responding (Rojas-Carvajal et al., 2021). Finally, it is emerging that stress and stress-related disorders have differential impacts on various neuronal subpopulations, especially the so-far largely overlooked important role of glial cell populations as microglia or astrocytes in relation to stress (Balog et al., 2021; Sanguino-Gómez et al., 2021). The one-sided focus on male individuals especially in pre-clinical research in the past decades has hampered our understanding of the stress biology, which is highlighted in a number of papers in this special issue (Balog et al., 2021; Flanigan & Kash, 2020; Levis et al., 2021). Stress is a cross-species phenomenon throughout phylogeny that can have important consequences both for individuals as well as for societies. [Extracted from the article]

Objective: The aim of the study was the quantification of circulating tumour cells (CTCs) in differentiated thyroid cancer (DTC) patients before and 6 weeks after radioiodine therapy (RIT). Context: Circulating tumour cells (CTCs) were described more recently in cancer patients, mostly correlating with poor outcome and advanced metastases. Design: Peripheral blood for identification and quantification of CTC before RIT or/and 6 weeks after RIT was provided by 55 DTC patients that received RIT for remnant tissue ablation. Patients: 13 follicular thyroid cancer (FTC) patients, 31 papillary thyroid cancer (PTC) patients and 11 patients having the follicular variant PTC (FV‐PTC) were included. Measurements: Peripheral blood mononuclear cells (PBMCs) were isolated and EpCAM‐positive CTCs were counted by immune fluorescent staining. Results: A CTC positivity of 31.8% before RIT could be observed. Six weeks after RIT, the CTC positivity was reduced to 13.6%. Paired data at both time points of blood sampling could be gathered for n = 33 DTC patients. These patients had significantly higher CTC numbers before RIT than 6 weeks afterwards (0.27 ± 0.47 vs 0.05 ± 0.15, P =.0215). Additionally, significantly reduced CTC numbers were also demonstrated in pre‐RIT CTC‐positive patients (0.88 ± 0.43 vs 0.05 ± 0.16, P =.0039). Conclusion: Our results indicate a reducing effect on the number of CTCs by RIT. Therefore, CTC enumeration should be considered as efficient tool for treatment monitoring during RIT. [ABSTRACT FROM AUTHOR]

It is well-known that from 1963 Helmut Bauer was head of the department of neurology at the University of Göttingen and was one of the German pioneers in research into multiple sclerosis. During the years 1971–1972 he acted as president, later honorary president of the German Neurological Society (DGN), of which he also became honorary member in 1982. Almost unknown, however, is his career during the "Third Reich" and immediately after the war. After returning from the USA in 1932, he completed his medical studies in the German Reich. In 1940 he again acquired German citizenship, which has to be interpreted as an acknowledgement of the Nazi regime. He was initially active in the Foreign Department of the Reich Medical Council. In 1941 he joined the SS and served as member of the so-called Künsberg special commandos of the SS in France, Greece, and Italy as well as in the Baltic states and the Soviet Union (1941–1943). As a medical case officer, he was in charge of the confiscation of medical material and documents, even of healthcare institutions and of Jewish property. In 1943 and 1944 he worked as SS Captain (Hauptsturmführer) at the Research Center for Medicine in Foreign Countries and Settlement Biology and the Institute for Microbiology at Sachsenburg Castle near Frankenberg in Saxony, a joint establishment of the Wehrmacht, the Ministry of the Interior and the Robert Koch Institute in cooperation with the SS. In addition to the search for a vaccine against Yersinia pestis and the participation in war propaganda, Bauer's research unit was mainly concerned with the statistical evaluation of "racial examinations" of resettlers. After a short time as a prisoner of war (POW), Bauer had to undergo a denazification trial where he succeeded in being exonerated enabling him to pursue his medical career. Recent historical investigations have revealed that he was involved in military and racial hygiene (eugenics) crimes of the Nazis and therefore belonged to the group of persons who were active supporters of the political system. [ABSTRACT FROM AUTHOR]

• A multi-sphere assessment of ecosystem service provision. • Application of the multi-criteria decision analysis approach for land use changes. • Illustration of impacts and trade-offs between ecosystem services across Denmark. Close to 60 per cent of the Danish land area is used for arable farming. EU regulations as well as public preferences create increasing pressures for changing agricultural land use in a more environmentally sustainable direction incorporating the multiple ecosystem services affected by agriculture. In this paper we present a spatially explicit multi-criteria decision analysis model which describes the trade-offs between the rent obtained from land in agricultural use on the one hand and selected ecosystem services on the other. The model is based on an extensive geographical dataset. This include maps on soil types, carbon content, sensitivity to nutrient losses, High Nature Value scores etc., which in combination with environmental criteria facilitates the ranking of all agricultural fields in Denmark according to their current overall worth to society in terms of land rent as well as other ecosystem services. Picking from a ranked list, we identify areas that may be considered efficient candidates for land use change considerations. Subsequently, the model is applied to identify suitable candidate areas for land use change in scenarios attaching different weights to various environmental services. In this way, four scenarios for Danish agricultural land use in 2050 are analysed. The results highlight that the possible realization of each of these mutually exclusive scenarios will require decision makers to consider very different development paths and land use changes for the Danish agricultural area. [ABSTRACT FROM AUTHOR]

Efficient biodiversity conservation may rest on support for transnational cooperation; particularly for migratory species. Support for transnational conservation efforts may hinge on key issues like the potential outcomes and whether any collaboration aspect is highlighted. We designed an experiment focused on conservation of open land habitats in Denmark and the Netherlands. We tested how support of Danish households depends on framing in a context of possible losses of habitats and on possible contributions from Dutch households to the conservation case. We further tested for presence of loss aversion in outcomes and income. We found that the willingness-to-pay (WTP) for gains in open land habitats at home tended to increase when habitat losses were possible. Framing in the context of others, Dutch households, contributing consistently affected Danes' WTP for increasing protected habitat areas and for avoiding habitat losses. And the less Dutch households contributed, the more Danish households contributed with the converse also being true. Our results suggest that overall support for habitat conservation for migratory birds may be higher in cases where a risk of habitat losses exists. Results also suggest that support for conservation at home increase when respondents perceive that they share the challenge with other countries. • We find higher WTP for habitat increases, when habitat losses are also an option. • We find higher WTP for conservation, when burdens are shared across nations. • We find evidence of higher WTP for avoided losses than gains in habitat area. • We find evidence for loss aversion in income. • Conservation at home is preferred over conservation abroad. [ABSTRACT FROM AUTHOR]

Abstract The German physician Maximilian Borst (1869–1946) was undoubtedly one of the best-known and most renowned pathologists worldwide of his time. His work on tissue transplantation and cancer research set international standards. Furthermore his career in Germany was also almost unprecedented: He was appointed to a chair of pathology at a young age during the German Reich, continued his career seamlessly in the Weimar Republic and was even able to expand his career in the Third Reich. Finally, after the end of the Nazi regime, he was among the group of university teachers who were considered to be politically unencumbered. The background to this favourable classification – and to Borst's unbroken career – was the fact that he had not joined the NSDAP in the Third Reich. Accordingly, he was considered apolitical. But is this reading tenable in the case of Maximilian Borst and does it stand up to critical historical scrutiny? What was the nature of Borst's relationship to the Nazi regime and what was his political position? It is precisely these questions that are the focus of this article. The study is primarily based on archival sources. In addition, a systematic analysis was performed of the relevant international research literature on Max Borst's life and work and on the history of cancer research in the Third Reich in particular. The paper comes to the conclusion that Borst demonstrably served the Nazi regime after 1933. However, Borst's closeness and loyalty to the National Socialists was not revealed through formal memberships of organisations such as the NSDAP or the SS, but rather through a number of influential positions in the field of health policy which were offered to him during the Third Reich. There is no doubt that the transfer of such functions presupposed "political reliability" and "loyalty to the line" on the part of the officeholder. Borst's often assumed inner distance to politics in general and to National Socialism in particular is just as incorrect as his alleged harassment by the Nazi bureaucratic system. [ABSTRACT FROM AUTHOR]

Abstract International efforts to protect biodiversity depend on transnational collaboration and on public support for transnational policies to be implemented. Yet, we know little about what may compel citizens to support such transnational conservation efforts. In this paper, we design a lab-in-the-field experiment to explore how different framings and information about support shared across borders affect a citizen's conservation donations. Using a dictator game, we ask for donations from individuals in Denmark, Spain, and Ghana for the protection of natural habitats of the migratory Montagu's Harrier (Circus pygargus). We focus on citizens from Denmark, Spain and Ghana since these countries lie along the harrier's migratory route. We found that information affects donation behavior, albeit differently in each country. Our Danish and Ghanaian participants contributed more when (1) pre-donation information stressed that transnational collaboration is needed, and (2) they were told that a measure of their group's donation would be forwarded to other participants. In contrast, our Spanish participants donated less overall and were insensitive to the information treatments. The results document large differences across countries in supporting behavior in such transnational conservation settings and could influence how international conservation organizations organize and shape fundraising for their work. Highlights • Information on the need for transnational collaboration affects donation behavior. • Awareness of own donations being forwarded to others increases donations. • Donation levels in own and other countries have no clear impact on own donations. [ABSTRACT FROM AUTHOR]

The use of node coordinates as design variables in shape optimization offers a larger design space than computer-aided design (CAD)-based shape parameterizations. It also allows for the optimization of legacy designs, i.e., a finite element mesh from an existing design can be readily optimized to meet new performance requirements without involving a CAD model. However, it is well known that the node coordinate parameterization method is fraught with numerical difficulties, which makes it impractical to use. This has led to several of “parameter-free” shape optimization methods that seek the advantages and avoid the pitfalls of the naïve node coordinate parameterization method. These methods come in two main varieties: sensitivity filtering (or gradient smoothing) and consistent filtering. The latter is analogous to the density filter method used in topology optimization (TO). Herein, we use the PDE filter from TO and energy-based filters to implement consistent shape optimization filtering schemes easily and efficiently. Numerical experiments demonstrate that consistent methods are more robust than sensitivity filtering methods. [ABSTRACT FROM AUTHOR]

Multifocal visual evoked potential (mf-VEP) represents a new approach to the classical full field (ff-)VEP with separate responses from up to 60 sectors of the visual field. A thorough literature survey of the use of mf-VEP in optic neuritis (ON) and multiple sclerosis (MS) is presented (38 published studies were retrieved). Mf-VEP provides direct topographical information of specific lesions and facilitates investigations on structural-functional correlations thus providing new methods for exploring the interplay between demyelination, atrophy and remyelination in MS. Good correlation was shown between mf-VEP and OCT, ff-VEP, MRI (MTR, DTI), 30-2 standard automated perimetry and low-contrast-visual acuity. All but one study showed superior sensitivity and specificity compared to ff-VEP, especially with regards to small, peripheral lesions or lesions of the upper visual field. Mf-VEP has shown superior sensitivity and specificity than established methods in diagnosing optic nerve lesions and tracking functional recovery following lesions. Abnormal mf-VEP responses in the fellow, non-ON afflicted eye may predict MS risk in ON patients. No standardization currently exists and no direct comparisons in ON and MS between at least 5 different commercially available mf-VEP systems have so far been published. Despite these limitations, mf-VEP is a promising new tool of diagnostic and prognostic value of mf-VEP in ON and MS. [ABSTRACT FROM AUTHOR]

Monocarboxylate transporter 8 (MCT8) equilibrates thyroid hormones between the extra- and the intracellular sides. MCT8 exists either with a short or a long N-terminus, but potential functional differences between both variants are yet not known. We, therefore, generated MCT8 constructs which are different in N-terminal length: MCT8(1–613), MCT8(25–613), MCT8(49–613) and MCT8(75–613). The M75G substitution prevents translation of MCT8(75–613) and ensures expression of full-length MCT8 protein. The K56G substitution was made to prevent ubiquitinylation. Cell-surface expression, localization and proteasomal degradation were investigated using C-terminally GFP-tagged MCT8 constructs (HEK293 and MDCK1 cells) and oligomerization capacity was determined using N-terminally HA- and C-terminally FLAG-tagged MCT8 constructs (COS7 cells). MCT8(1–613)-GFP showed a lower protein expression than the shorter MCT8(75–613)-GFP protein. The proteasome inhibitor lactacystin increased MCT8(1–613)-GFP protein amount, suggesting proteasomal degradation of MCT8 with the long N-terminus. Ubiquitin conjugation of MCT8(1–613)-GFP was found by immuno-precipitation. A diminished ubiquitin conjugation caused by K56G substitution resulted in increased MCT8(1–613)-GFP protein expression. Sandwich ELISA was performed to investigate if the bands at higher molecular weight observed in Western blot analysis are due to MCT8 oligomerization, which was indeed shown. Our data imply a role of the long N-terminus of MCT8 as target of ubiquitin-dependent proteasomal degradation affecting MCT8 amount and subsequently oligomerization capacity. [ABSTRACT FROM AUTHOR]

Using solution-casting method, binary blends of chitosan (CS) and poly (ethylene oxide) (PEO 100,000) containing Au nanoparticles (AuNPs) were prepared. Shifts in the melting temperature ( T m ) and crystallization temperature ( T c ) values for CS/PEO and CS/PEO/AuNPs blends were observed by calorimetric analysis. In general, CS/PEO/AuNPs blends tended to decompose at higher temperatures than neat polymers. From the FT-IR spectra, shifts in the main signals, such as −NH 2 , −OH and C O C, were detected in the blends and were attributed to the polymer interactions and the incorporation of gold nanoparticles. In addition, the analysis of the blend topographies by atomic force microscopy (AFM) showed that at a higher CS content, more homogenous surfaces were observed. This behavior was attributed to the interactions present in the CS/PEO/AuNPs blends. Finally, theoretical analyses helped to confirm that the gold nanoparticles would be preferentially adsorbed onto the chitosan microdomains due to the interactions between acetyl and hydroxyl groups and Au atoms. [ABSTRACT FROM AUTHOR]

The association between an increased uptake of isoflavones and a reduced frequency of menopausal hot flushes was first described in 1992, based on a lower incidence of hot flushes in countries with a high consumption of soy. Since then, numerous clinical trials with various sources of isoflavones including soy and red clover have been presented, with practically all of the studies with adequate design delivering an outcome in favour of isoflavone supplementation. An in-depth risk assessment (EFSA 2015) concludes that the amply available human data does not indicate any suspected harmful effects from a potential interaction of isoflavones with hormone-sensitive tissues in the mammary gland, the uterus and the thyroid gland. Safety was ascertained with long-term intake of up to 150 mg isoflavones per day ingested for the duration of at least 3 years. Moreover, high isoflavone intake was found to have preventive effects with respect to breast cancer. Clinical findings indicate potential benefits of isoflavone exposure even during breast cancer treatment with tamoxifen or anastrozole. [ABSTRACT FROM AUTHOR]

FeMn/Co thin-films, a purely metallic exchange-bias system, were prepared on (100)-oriented MgO single crystals. The layers were grown by molecular beam epitaxy (MBE). The crystalline and magnetic properties could be tuned by using sputtered Pt buffer layers deposited at variable temperatures. A transition of the crystalline orientation from (111)-terminated layers at lower deposition temperatures to (100)-terminated layers at temperatures higher than 950 K was established and the impact on the magnetic sample properties was investigated. Here, the detailed sample preparation process is shown together with low energy electron diffraction (LEED), medium energy electron diffraction (MEED), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD) and transmission electron microscopy (TEM) measurements revealing the samples structure and composition. The crystalline orientation of Pt was imprinted to the magnetic layer stack and clearly influenced the exchange-bias (EB) and coercive field ( HC) as shown by superconducting quantum interference device (SQUID) and magneto-optical Kerr effect (MOKE) measurements. Furthermore, a correlation between the crystallite size and the temperature dependent magnetic properties could be identified. [ABSTRACT FROM AUTHOR]

As a consequence, stress-induced illnesses are further on the rise and new advances in the field of stress research are dearly needed. The authors propose that the stress response is continuously fine-tuned by neuronal activity, shaping the diversity of stress responses based on prior experience. [Extracted from the article]

The article presents a report from an October 7-10, 2014 conference in Aachen, Germany on medical associations in Nazi Germany organized by the Institut für Geschichte, Theorie und Ethik der Medizin medical ethics institute at the Universitätsklinikum der Rheinisch-Westfälischen Technischen Hochschule Aachen clinic. Topics of presentations delivered included medical ethics in the Saar Protectorate, the influence of Nazism on the provision of public health services in Germany, and the influence of the 1933 annexation of Austria on medical societies there.

First-order reversal curves (FORC) are a powerful method for magnetic sample characterization, separating all magnetic states of an investigated system according to their coercivity and internal magnetic interactions. A major drawback of using measurement techniques like VSM or SQUID, typically applied for FORC acquisition, is the long measurement time, limiting the resolution and the number of measurements due to time constraints. Faster techniques like MOKE result in problems regarding measurement stability over the curse of the acquisition of many minor loops, due to drift and non-absolute magnetization values. Here, we present an approach using a specialized field shape providing two anchor points for each minor loop for applying the magneto-optical Kerr effect (MOKE) technique to FORC measurements. This results in a high field resolution while keeping the total acquisition time to only a few minutes. MOKE FORC measurements are exemplarily applied to a simple permalloy film, an exchange-bias system, and a Gd/Fe multilayer system with perpendicular magnetic anisotropy, showcasing the versatility of the method. [ABSTRACT FROM AUTHOR]

The article offers a report from a July 14-20, 2013 conference in Ulm, Germany on the automation of care for older people. Topics of presentations delivered included the history and future of the epidemiology associated with population aging, images of older people in art from the Middle Ages until the 21st century, and the history of equipment used by older people to mitigate the effects of aging or illness.

The article presents a report on a conference on disability studies and history, held in Aachen, Germany, on December 7, 2012. Topics of discussion included prosthetic teeth, galvanism and electrotherapy for the treatment of deafness, and the representation of disabilities and people with disabilities in film.

Abstract: So far, metal oxide semiconductor field-effect transistors (MOSFETs) have been fabricated using either optical lithography or imprint lithography with an alignment step between the different layers. Here, we report on the new process for the fabrication of top gate MOSFETs where the number of fabrication steps is reduced significantly. The 3D topography of a top gate MOSFET using as primary master is inversely replicated into a flexible mold that is subsequently transferred to the imprint resist layer. By reactive ion etching, this self aligned 3D pattern is transferred into the underlying semiconductor stack creating functional transistor structures. Preliminary electrical characterizations demonstrate fully operational transistor functions. [Copyright &y& Elsevier]

Stress is a normal response to situational pressures or demands. Exposure to stress activates the hypothalamic-pituitary-adrenal (HPA) axis and leads to the release of corticosteroids, which act in the brain via two distinct receptors: mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Persistent HPA axis overactivation or dysregulation can disrupt an individual's homeostasis, thereby contributing to an increased risk for mental illness. On the other hand, successful coping with stressful events involves adaptive and cognitive processes in the brain that render individuals more resilient to similar stressors in the future. Here we review the role of the MR in these processes, starting with an overview of the physiological structure, ligand binding, and expression of MR, and further summarizing its role in the brain, its relevance to psychiatric disorders, and related rodent studies. Given the central role of MR in cognitive and emotional functioning, and its importance as a target for promoting resilience, future research should investigate how MR modulation can be used to alleviate disturbances in emotion and behavior, as well as cognitive impairment, in patients with stress-related psychiatric disorders. [ABSTRACT FROM AUTHOR]

Abstract: This paper integrates the cumulative stress hypothesis with the mismatch hypothesis, taking into account individual differences in sensitivity to programming. According to the cumulative stress hypothesis, individuals are more likely to suffer from disease as adversity accumulates. According to the mismatch hypothesis, individuals are more likely to suffer from disease if a mismatch occurs between the early programming environment and the later adult environment. These seemingly contradicting hypotheses are integrated into a new model proposing that the cumulative stress hypothesis applies to individuals who were not or only to a small extent programmed by their early environment, while the mismatch hypothesis applies to individuals who experienced strong programming effects. Evidence for the main effects of adversity as well as evidence for the interaction between adversity in early and later life is presented from human observational studies and animal models. Next, convincing evidence for individual differences in sensitivity to programming is presented. We extensively discuss how our integrated model can be tested empirically in animal models and human studies, inviting researchers to test this model. Furthermore, this integrated model should tempt clinicians and other intervenors to interpret symptoms as possible adaptations from an evolutionary biology perspective. [Copyright &y& Elsevier]

Stress has been identified as a major causal factor for many mental disorders. However, our knowledge about the chain of molecular and cellular events translating stress experience into altered behavior is still rather scant. Here, we have characterized a murine ortholog of the putative tumor suppressor gene DRR1 as a unique stress-induced protein in brain. It binds to actin, promotes bundling and stabilization of actin filaments, and impacts on actin-dependent neurite outgrowth. Endogenous DRR1 localizes to some, but not all, synapses, with preference for the presynaptic region. Hippocampal virus-mediated enhancement of DRR1 expression reduced spine density, diminished the probability of synaptic glutamate release, and altered cognitive performance. DRR1 emerges as a protein to link stress with actin dynamics, which in addition is able to act on synaptic function and cognition. [ABSTRACT FROM AUTHOR]

Summary: Early life stress is one of the best characterized risk factors for psychiatric disorders, including depression, and many animal models have therefore studied the long-term physiological and behavioural consequences of early life stress. In most approaches a very deterministic view of adverse experiences early in life prevails, linking these events inevitably with later pathology. By summarizing literature on early life programming and adaptive phenotypic plasticity the current review proposes that early life challenges may induce changes that prepare an individual for life in a more hostile environment and are therefore predominantly beneficial. Adult diseases as depression might thus not be promoted by early life adversity per se, but by a mismatch of the programmed and the later actual environment in combination with a more vulnerable or resilient genetic predisposition. The present review further discusses the ability of currently available animal models for depression to investigate this novel hypothesis. Finally, a number of criteria and research strategies are outlined that would be necessary to address the mismatch hypothesis of depression. [ABSTRACT FROM AUTHOR]

Rationale: While human depressive illness is indeed uniquely human, many of its symptoms may be modeled in rodents. Based on human etiology, the assumption has been made that depression-like behavior in rats and mice can be modulated by some of the powerful early life programming effects that are known to occur after manipulations in the first weeks of life. Objective: Here we review the evidence that is available in literature for early life manipulation as risk factors for the development of depression-like symptoms such as anhedonia, passive coping strategies, and neuroendocrine changes. Early life paradigms that were evaluated include early handling, separation, and deprivation protocols, as well as enriched and impoverished environments. We have also included a small number of stress-related pharmacological models. Results: We find that for most early life paradigms per se, the actual validity for depression is limited. A number of models have not been tested with respect to classical depression-like behaviors, while in many cases, the outcome of such experiments is variable and depends on strain and additional factors. Conclusion: Because programming effects confer vulnerability rather than disease, a number of paradigms hold promise for usefulness in depression research, in combination with the proper genetic background and adult life challenges. [ABSTRACT FROM AUTHOR]

Increased vulnerability to aversive experiences is one of the main risk factors for stress-related psychiatric disorders as major depression. However, the molecular bases of vulnerability, on the one hand, and stress resilience, on the other hand, are still not understood. Increasing clinical and preclinical evidence suggests a central involvement of the glutamatergic system in the pathogenesis of major depression. Using a mouse paradigm, modeling increased stress vulnerability and depression-like symptoms in a genetically diverse outbred strain, and we tested the hypothesis that differences in AMPA receptor function may be linked to individual variations in stress vulnerability. Vulnerable and resilient animals differed significantly in their dorsal hippocampal AMPA receptor expression and AMPA receptor binding. Treatment with an AMPA receptor potentiator during the stress exposure prevented the lasting effects of chronic social stress exposure on physiological, neuroendocrine, and behavioral parameters. In addition, spatial short-termmemory, an AMPA receptor-dependent behavior, was found to be predictive of individual stress vulnerability and response to AMPA potentiator treatment. Finally, we provide evidence that genetic variations in the AMPA receptor subunit GluR1 are linked to the vulnerable phenotype. Therefore, we propose genetic variations in the AMPA receptor system to shape individual stress vulnerability. Those individual differences can be predicted by the assessment of short-term memory, thereby opening up the possibility for a specific treatment by enhancing AMPA receptor function. [ABSTRACT FROM AUTHOR]

Abstract: Early life stress is one of the most explicit and undisputed environmental risk factors for disease later in life, including metabolic and psychiatric diseases. The developmental timing and context of stressful stimuli is thereby essential and determines the adaptive or maladaptive consequences. This review, which honors the invaluable accomplishments of one of the pioneers in the field, the late Seymour “Gig” Levine, focuses on the contribution of mouse models to the understanding of the molecular mechanisms that govern the acute and persistent effects of early life stress. The importance of the postnatal period and the complex role of maternal care in regulating the offspring''s stress system activity are specifically addressed. Further, I discuss the possible molecular mechanisms that may be responsible for the persistent effects of early life stress, including the important issue of resilience and susceptibility to adverse life events. [Copyright &y& Elsevier]

Over the last decades the burden of disease in Western countries has shifted from comparably easily treated infectious diseases to more complex diseases, such as the metabolic syndrome, cardiovascular disease, and psychiatric disorders. A common characteristic of these illnesses is the interplay of multiple genetic and nongenetic factors, which eventually results in the manifestation of disease symptoms. Large-scale epidemiological studies in humans have resulted in the identification of various environmental and genetic risk factors, which contribute to the onset, duration, and severity of disease. While tremendous progress has been made, it is still impossible to predict which combination of risk factors will result in the manifestation of a specific illness. This lack of knowledge is also frequently reflected in inadequate treatment strategies, which mainly focus on symptom reversal rather than targeting the cause of the diseases. One of the most prominent environmental risk factors described for numerous diseases is chronic exposure to stressful situations. In this paper we address clinical and preclinical evidence of chronic stress as a risk factor for disease and introduce a novel, high-throughput mouse model for chronic social stress. We can show that this model has a high degree of construct, face, and predictive validity in terms of physiological, behavioral, and gene expression changes. We further illustrate how novel animal models of chronic social stress can help to unravel the complex interaction of individual genetic vulnerability and environmental risk factors. [ABSTRACT FROM AUTHOR]

Abstract: The function and regulation of the hypothalamic–pituitary–adrenal (HPA) axis during ontogeny differs markedly from the situation in adult animals. Postnatally mice undergo a so-called stress hypo-responsive period, which is characterized by a relative inability of mild stressors to induce a marked corticosterone response. Steroid receptor coactivators (SRCs) have been shown to influence the function of the HPA axis in adult animals by interacting with steroid receptors as the mineralocorticoid and the glucocorticoid receptor. Here we test the hypothesis that expression changes of the three identified SRC genes (SRC1, SRC2 and SRC3) correlate with differences in HPA axis activity during postnatal development. First, we mapped the ontogeny of the three SRCs during postnatal development in the hippocampus. We found a time- and region-specific regulation of gene expression, which was specific for each SRC. However, there was no relation between the age-dependent stress system activity and the expression levels of the SRCs. Further, we studied the acute regulation of the three SRCs following maternal deprivation in 9-day-old wild-type or CRH receptor type 1 (CRHr1) knockout mice. Under these conditions, no differential expression of any of the tested SRCs could be detected. Thus, while it seems likely that their varying abundance throughout postnatal life affects steroid receptor function in the different hippocampal subregions, acute changes of HPA axis activity or reactivity are not mediated by hippocampal changes in expression of this coactivator family. [Copyright &y& Elsevier]

Comments on a study on the hepatotoxicity of kava extracts. Background of toxicologic studies with kava extract and isolated kavalactones; Details on kavalactone-free preparations; Information on the acute toxicity of kavalactones in animal experiments.

In this study we describe in 9- and 18-day-old CD1 mice (i) the basal and stress-induced activity of markers of the HPA system in blood, brain and pituitary, (ii) the effects of a 24-h maternal deprivation and (iii) the influence of anogenital stimulation (stroking) in deprived pups on these markers. We found low basal concentrations of ACTH and corticosterone at postnatal day (pnd) 9 and no or little response to a mild stressor at this age, confirming the existence of a SHRP in mice. At pnd 18 the mice displayed an adult-like ACTH and corticosterone response following a mild stressor. Maternal deprivation resulted in enhanced basal and stress levels of corticosterone at both ages. Interestingly, basal ACTH levels were elevated following maternal deprivation at pnd 9. At pnd 18 maternal deprivation resulted in a blunted ACTH response. Maternal deprivation resulted in a down-regulation of GR, MR, CRH and POMC transcript in the brain. However, maternally deprived 18-day-old pups displayed increased levels of CRH and POMC transcript, while GR and MR mRNA was also down-regulated. Anogenital stroking could reverse maternal deprivation effects on ACTH and MR mRNA, but not CRH mRNA. We conclude that (i) at the two measured time points the HPA axis develops similar in mice as in rats, (ii) maternal deprivation has pronounced effects in mice, which are similar to that found in the rat and (iii) there are a number of significant differences, which mainly concern the central CRH–ACTH components of the axis. [Copyright &y& Elsevier]

Inactivation of the retinoblastoma (Rb) protein caused by gene mutation, association with oncoproteins from small DNA viruses, mutational inactivation of p16Ink4a, or overexpression of cyclin D is a common feature of many human cancer cells and is causally associated with the aberrant proliferation control of cancer cells; whereas normal cells maintain an integrated cell cycle machinery and are subject to cell cycle checkpoint control by cyclin-dependent kinase (CDK) inhibitors (CKIs). To determine whether this difference can be translated into a therapeutic advantage to protect normal cells from adverse cytotoxicity caused by chemotherapy, we established cell model systems for ecdysone-inducible expression of p16Ink4a, p21Waf1, and p27Kip1 in one CKI-responsive cell line (A431 human vulvar epidermoid carcinoma cells with functional Rb) and one CKI-unresponsive cell line (SiHa human cervical cancer cells with nonfunctional Rb). Expression of p16Ink4a, p21Waf1, or p27Kip1 in both SiHa and A431 cells strongly inhibited CDK2 activity, indicating functional expression of the CDK inhibitors in both cell lines. However, only in A431 cells did expression of p16Ink4a, p21Waf1, or p27Kip1 cause Rb dephosphorylation, arrest cell cycle traversal, and potently inhibit cell proliferation. Induction of p16Ink4a, p21Waf1, or p27Kip1 in SiHa cells failed to cause Rb dephosphorylation or to arrest cell cycle traversal, and such induction only minimally inhibited cell proliferation. We then compared the chemosensitivity of clones derived from these two cell lines when the CKIs were and were not induced. Induction of p16Ink4a, p21Waf1, or p27Kip1 conferred strong resistance to paclitaxel- or cisplatin-mediated cytotoxicity on the CKI-responsive A431 cells but not on the CKI-unresponsive SiHa cells. Our... [ABSTRACT FROM AUTHOR]

The impact of the cyclin dependent kinase (CDK) inhibitors p21Waf1 and p27Kip1 on paclitaxel-mediated cytotoxicity was investigated in RKO human colon adenocarcinoma cells with the ecdysone-inducible expression of p21Waf1 or p27Kip1. Ectopic expression of p27Kip1 arrested cells at G1 phase, whereas p21Waf1 expression arrested cells at G1 and G2. Expression of p21Waf1 after paclitaxel treatment produced much greater resistance to paclitaxel than did expression of p27Kip1. We attributed this difference to the additional block at G2 induced by p21Waf1, which prevented cells from entering M phase and becoming paclitaxel susceptible. Expression of p21Waf1 inhibited p34cdc2 activity and markedly reduced paclitaxel-mediated mitotic arrest, from 87.5 to 23%. In contrast, p27Kip1 expression also inhibited p34cdc2 but reduced mitotic arrest only slightly, from 87.4 to 74.5%. We concluded that the G2 block produced by p21Waf1, but not by p27Kip1, contributed to their unequal modulation of sensitivity to paclitaxel-mediated apoptosis in RKO cells, and there is no causal relationship between paclitaxel-mediated cytotoxicity and elevation of p34cdc2 activity. Oncogene (2000) 19, 2423–2429 [ABSTRACT FROM AUTHOR]

This study tested if a high-resolution, multi-modal, multi-scale retinal imaging instrument can provide novel information about structural abnormalities in vivo. The study examined 11 patients with very mild to moderate non-proliferative diabetic retinopathy (NPDR) and 10 healthy subjects using fundus photography, optical coherence tomography (OCT), OCT angiography (OCTA), adaptive optics scanning laser ophthalmoscopy (AO-SLO), adaptive optics OCT and OCTA (AO-OCT(A)). Of 21 eyes of 11 patients, 11 had very mild NPDR, 8 had mild NPDR, 2 had moderate NPDR, and 1 had no retinopathy. Using AO-SLO, capillary looping, inflections and dilations were detected in 8 patients with very mild or mild NPDR, and microaneurysms containing hyperreflective granular elements were visible in 9 patients with mild or moderate NPDR. Most of the abnormalities were seen to be perfused in the corresponding OCTA scans while a few capillary loops appeared to be occluded or perfused at a non-detectable flow rate, possibly because of hypoperfusion. In one patient with moderate NPDR, non-perfused capillaries, also called ghost vessels, were identified by alignment of corresponding en face AO-OCT and AO-OCTA images. The combination of multiple non-invasive imaging methods could identify prominent microscopic abnormalities in diabetic retinopathy earlier and more detailed than conventional fundus imaging devices. [ABSTRACT FROM AUTHOR]

The Hypothalmic-Pituitary-Adrenal axis also known as the HPA axis is central to stress response. It also acts as the relay center between the body and the brain. We analysed hypothalamic proteome from mice subjected to chronic social defeat paradigm using iTRAQ based quantitative proteomics to identify changes associated with stress response. We identified greater than 2000 proteins after processing our samples analysed through Q-Exactive (Thermo) and Orbitrap Velos (Thermo) at 5% FDR. Analysis of data procured from the runs showed that the proteins whose levels were affected belonged primarily to mitochondrial and metabolic processes, translation, complement pathway among others. We also found increased levels of fibrinogen, myelin basic protein (MBP) and neurofilaments (NEFL, NEFM, NEFH) in the hypothalamus from socially defeated mice. Interestingly, research indicates that these proteins are upregulated in blood and CSF of subjects exposed to trauma and stress. Since hypothalamus secreted proteins can be found in blood and CSF, their utility as biomarkers in depression holds an impressive probability and should be validated in clinical samples. [ABSTRACT FROM AUTHOR]

The Jewish scientist Robert Meyer received worldwide professional recognition as a pioneer gynecopathologist. Before his death, he wrote a memoir in which he gave an entirely positive assessment of his life. The latter, however, is at odds with the fact that he was disenfranchised by the National Socialists and driven into emigration. But even before Hitler's seizure of power, he had to cope with several strokes in private as well as in professional life. This article takes these apparent inconsistencies as an occasion for a fundamental analysis of Robert Meyer's life and work. Special attention is paid to his scientific achievements, but also to repressive experiences in the Third Reich, the background of his emigration and his specific handling of these adversities. Various archival documents, Meyer's memoirs, and other contemporary writings by and about Robert Meyer and about the development of the field of gynecopathology serve as central sources. The study concludes that Meyer made fundamental contributions to the embryology of the vagina, ovarian tumors, cancer diagnosis, endometriosis, and genital and fetal abnormalities. Despite his scientific merits, he was never granted a regular professorship – mainly, because he was professionally caught between two stools (gynecology and pathology), but also due to low career ambition. Nevertheless, thanks to influential supporters, he was able to hold out in Germany until 1939, when he emigrated to the United States. Meyer considered his life "beautiful" despite many misfortunes because he defined happiness in life primarily in terms of fulfilling personal relationships and was willing to accept life as it comes. In addition, he found distraction and fulfillment in his scientific work. [ABSTRACT FROM AUTHOR]

Kava (Piper methysticum G. Forst. f.) is by far the most important plant used in the islands of Melanesia, Polynesia and Micronesia for its relaxing effects. Kava drinking is a pillar of South Pacific societies and is also the foundation of their economies. Preparations of kava extract as herbal medicinal drugs were banned in Germany in 2002 and again in 2019, with dramatic consequences for the South Pacific economies. In 2002, the major regulatory argument for the ban of kava was safety issues. In 2019, the assessment report of the European Medicines Agency's Herbal Medicinal Product Committee (HMPC) justified a negative benefit-to-risk ratio by a supposed lack of efficacy of ethanolic extracts for an indication of which kava extract preparations never had an approval. In this HMPC report the efficacy in the approved indications 'nervous anxiety, tension and restlessness' was attributed to the extract branded as 'WS 1490', which was assumed to have been prepared with acetone as an extraction solvent. In addition to this change of indication and the attribution of efficacy to acetone kava extract alone, the German health authorities and the HMPC still refuse to discuss quality issues as a likely factor impacting drug safety. The first case reports of liver toxicity were observed with an acetone extract in a timely relationship with the introduction of 'two-day kava' instead of 'noble kava' as used in ethanolic kava extracts. The correlation between clinical benefits and the type of extract preparation was examined. In order to identify the types of kava material and extracts used in clinical trials, the respective publications were compared with regulatory databases and protocols of a German regulatory advisory board. The comparison reveals inconsistencies in the regulatory decisions. In all studies with WS 1490, the evidence points to the use of an ethanolic extract. The efficacy of kava extract for the approved indication was clearly demonstrated. The HMPC report and the recent renewed German regulatory ban of kava therefore require major revision, which should include the impact of the use of "two-day kava" on drug safety. Such a revision could contribute to restoring the reputation of "noble kava" on the international markets. Image 1 • Kava extract preparations are efficacious in nervous anxiety, tension and restlessness. • The HMPC's assumption of generalized anxiety as the indication of kava is unfounded. • The attribution of the clinical evidence to acetone extracts must be questioned. • There is evidence that the branded extract "WS 1490" was prepared with ethanol. • There are inconsistencies in the procedures, which led to the prohibition of kava. • The substitution of noble with two-day kava has never been examined. [ABSTRACT FROM AUTHOR]

Cytotoxic strategies which are directed to tumor-associated antigens might be most beneficial for cancer patients with minimal tumor load such as in an adjuvant setting after initial therapy. We have recently described a highly potent single chain antibody-toxin, scFv(14E1)-ETA, which consists of the variable domains of the antibody 14E1 genetically fused to a truncated form of Pseudomonas exotoxin A. ScFv(14E1)-ETA specifically recognizes the human epidermal growth factor receptor (EGFR) and the oncogenically activated receptor variant EGFRvIII, which have been implicated in the development of various human malignancies. Here we have investigated the antimetastatic activity of bacterially expressed scFv(14E1)-ETA and its disulfide-stabilized derivative ds-scFv(14E1)-ETA in a novel model for disseminated disease which is based on murine renal carcinoma cells subsequently transfected with the E. coli β-galactosidase gene, and human full-length or variant EGFR cDNAs. Intravenous injection of these Renca-lacZ/EGFR and Renca-lacZ/EGFRvIII cells in syngenic Balb/c mice led to the formation of pulmonary metastases which were readily detectable upon excision of the lungs and X-gal staining. Systemic treatment of mice with scFv(14E1)-ETA resulted in the complete suppression of Renca-lacZ/EGFRvIII metastasis formation and drastically reduced the number of pulmonary Renca-lacZ/EGFR tumor nodules. The ds-scFv(14E1)-ETA derivative where the antibody variable regions are connected by an artificial disulfide bond displayed improved thermal stability at physiological temperature but due to reduced cytotoxic activity was less potent than the original scFv(14E1)-ETA in metastasis suppression. [ABSTRACT FROM AUTHOR]

European Union guidelines indiscriminately discuss a permitted daily exposure (PDE) for pyrrolizidine alkaloids (PA) of up to 0.007 μg/kg body weight for oral and for topical exposure to herbal medicinal products. In this study, lycopsamine served as a model substance for measuring the extent of skin permeation of PAs following the application of a spiked comfrey cream (Symphytum officinale s.l.) to abdominal skin from human donors in Franz diffusion cells. PAs could be excluded in the non-spiked cream with a limit of detection of 8 μg/kg. Only small amounts of the applied quantity of lycopsamine had migrated through the skin sample into the receptor cell side of the diffusion cell after 24 h. In five of six diffusion cells, there was no detectable lycopsamine within the skin and only 0.6 ± 0.4% of the applied dose in the receptor fluid. The theoretical skin penetration of 4.9% of the applied quantity of lycopsamine largely resulted from the worst case approach of assuming the presence of at least a quantity corresponding to the limit of detection – the true penetration is probably considerably lower. Even with the worst-case calculation, the currently discussed guidelines on PA overestimate the risk related to topical preparations. Image 1 • Comfrey (Symphytum officinale s.l.) may contain potentially toxic pyrrolizidine alkaloids (PA). • Medicinal comfrey (Symphytum x uplandicum Nyman) does not contain PA (limit of detection 8 μg/kg). • The PA lycopsamine (typical for the gender of comfrey) is poorly absorbed through human skin. • Regulatory limits calculated for systemic exposure are not applicable to topical preparations. • The low bioavailability of lycopsamine contributes to the safety of comfrey herb cream. [ABSTRACT FROM AUTHOR]