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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.forsciint.2007.01.027 Byline: Kathrin Yen (a)(b), Karl-Olof Lovblad (c), Eva Scheurer (a), Christoph Ozdoba (d), Michael J. Thali (a), Emin Aghayev (a), Christian Jackowski (a), Javier Anon (a)(d), Nathalie Frickey (e), Karin Zwygart (f), Joachim Weis (g), Richard Dirnhofer (a) Keywords: CT; MRI; Forensic imaging; Virtopsy; Post-mortem neuroradiology Abstract: Multislice-computed tomography (MSCT) and magnetic resonance imaging (MRI) are increasingly used for forensic purposes. Based on broad experience in clinical neuroimaging, post-mortem MSCT and MRI were performed in 57 forensic cases with the goal to evaluate the radiological methods concerning their usability for forensic head and brain examination. An experienced clinical radiologist evaluated the imaging data. The results were compared to the autopsy findings that served as the gold standard with regard to common forensic neurotrauma findings such as skull fractures, soft tissue lesions of the scalp, various forms of intracranial hemorrhage or signs of increased brain pressure. The sensitivity of the imaging methods ranged from 100% (e.g., heat-induced alterations, intracranial gas) to zero (e.g., mediobasal impression marks as a sign of increased brain pressure, plaques jaunes). The agreement between MRI and CT was 69%. The radiological methods prevalently failed in the detection of lesions smaller than 3mm of size, whereas they were generally satisfactory concerning the evaluation of intracranial hemorrhage. Due to its advanced 2D and 3D post-processing possibilities, CT in particular possessed certain advantages in comparison with autopsy with regard to forensic reconstruction. MRI showed forensically relevant findings not seen during autopsy in several cases. The partly limited sensitivity of imaging that was observed in this retrospective study was based on several factors: besides general technical limitations it became apparent that clinical radiologists require a sound basic forensic background in order to detect specific signs. Focused teaching sessions will be essential to improve the outcome in future examinations. On the other hand, the autopsy protocols should be further standardized to allow an exact comparison of imaging and autopsy data. In consideration of these facts, MRI and CT have the power to play an important role in future forensic neuropathological examination. Author Affiliation: (a) Institute of Forensic Medicine, University of Bern, 3012 Bern, Switzerland (b) Forensic Radiology Department, Center of Clinical-Theoretical Medicine, Medical University of Graz, Austria (c) Department of Neuroradiology, University of Geneva, Switzerland (d) Department of Radiology, Insel Hospitel Bern, Switzerland (e) Department of Anesthesiology and Intensive Care, University Hospital of Vienna, Austria (f) Department of Clinical Research, Magnetic Resonance Spectroscopy and Methodology, University of Bern, Switzerland (g) Institute of Neuropathology, RWTH University, Aachen, Germany Article History: Received 28 August 2006; Revised 15 December 2006; Accepted 21 January 2007 Article Note: (footnote) [star] Supported by grants from the Gebert-Ruef-Foundation, Basel, Switzerland, and from the Government of Vorarlberg, Bregenz, Austria.

Adult neurogenesis is a target for brain rejuvenation as well as regeneration in aging and disease. Numerous approaches showed efficacy to elevate neurogenesis in rodents, yet translation into therapies has not been achieved. Here, we introduce a novel human TGFβ-RII (Transforming Growth Factor—Receptor Type II) specific LNA-antisense oligonucleotide ("locked nucleotide acid"—"NVP-13"), which reduces TGFβ-RII expression and downstream receptor signaling in human neuronal precursor cells (ReNcell CX® cells) in vitro. After we injected cynomolgus non-human primates repeatedly i.th. with NVP-13 in a preclinical regulatory 13-week GLP-toxicity program, we could specifically downregulate TGFβ-RII mRNA and protein in vivo. Subsequently, we observed a dose-dependent upregulation of the neurogenic niche activity within the hippocampus and subventricular zone: human neural progenitor cells showed significantly (up to threefold over control) enhanced differentiation and cell numbers. NVP-13 treatment modulated canonical and non-canonical TGFβ pathways, such as MAPK and PI3K, as well as key transcription factors and epigenetic factors involved in stem cell maintenance, such as MEF2A and pFoxO3. The latter are also dysregulated in clinical neurodegeneration, such as amyotrophic lateral sclerosis. Here, we provide for the first time in vitro and in vivo evidence for a novel translatable approach to treat neurodegenerative disorders by modulating neurogenesis. [ABSTRACT FROM AUTHOR]

Abstract Aims To define the neurological and neuropathological alterations caused by SYNE1 mutations. Methods We describe 5 patients (3 males, 2 females; age 3–24 years) from 3 families. The diagnostic work-up included three muscle biopsies and two nerve biopsies in three of the cases. Results Three different phenotypes were discerned. Two patients showed progressive ataxia, mental retardation, neuropathy and radially deviated thumbs (spinocerebellar ataxia, SCAR, type 8 phenotype). Two patients had mild congenital myopathy with restrictive lung disease, clubfeet and thumb anomalies (myopathic arthrogryposis). One patient had congenital myopathy with dilated cardiomyopathy and adducted thumbs (Emery-Dreifuss Muscular Dystrophy, EDMD, type 4). Light microscopy of the three muscle biopsies revealed chronic non-necrotizing myopathy without rimmed vacuoles in all cases combined with neurogenic atrophy in one case. The two nerve biopsies showed predominantly axonal neuropathy with demyelinating features. Nuclear alterations, most notably lobulation and focal widening of the space between inner and outer leaflet of the nuclear envelope, were a prominent consistent feature of myonuclei and Schwann cell nuclei in each of the three muscle specimens and one nerve specimen that could be examined by electron microscopy. Conclusion Thumb abnormalities and nuclear envelope alterations are characteristic for SYNE 1 mutations. Schwann cell nuclei are affected, indicating that such nuclear envelope changes in glial cells contribute to the neurodegenerative phenotype in human nesprinopathies. Highlights • Thumb abnormalities in patients with SYNE1 mutations. • Lobulated myonuclei were a consistent ultrastructural feature. • Nuclear envelope pathology not only in myonuclei but also in Schwann cells nuclei. • Schwann cell nuclei are affected, indicating the neurodegenerative phenotype. [ABSTRACT FROM AUTHOR]

Objective: Although elevated levels of distress are supposed to constitute a need for psychosocial support, the relation between elevated distress and need for support does not appear to be straightforward. We aimed to determine cancer patients' perceived need for psychosocial support, and examine the relation of need to both self-reported emotional distress and the interview-based diagnosis of a mental disorder.Methods: In a multicenter, cross-sectional study in Germany, 4020 cancer patients (mean age 58 years, 51% women) were evaluated. We obtained self-reports of need for psychosocial support. We measured distress with the National Comprehensive Cancer Network (NCCN) Distress Thermometer (DT) and depressive symptoms with the Patient Health Questionnaire (PHQ-9). In a subsample, we evaluated the presence of a mental disorder using the Composite International Diagnostic Interview (CIDI).Results: 32.1% (95%-CI 30.6 to 33.6) of patients perceived a need for psychosocial support. Younger age, female sex, and higher education were associated with more needs, being married and living with a partner with fewer needs, respectively. While up to 51.2% of patients with elevated distress levels reported a need for psychosocial support, up to 26.1% of those without elevated distress levels perceived such a need. Results were similar across distress assessment methods.Conclusion: Our findings emphasize that the occurrence of mental distress is one important but not an exclusive factor among different motives to report the need for psychosocial support. We should thus consider multifaceted perspectives, facilitators and barriers when planning and implementing patient-centered psychosocial care services. [ABSTRACT FROM AUTHOR]

Mitochondrial "retrograde" signaling may stimulate organelle biogenesis as a compensatory adaptation to aberrant activity of the oxidative phosphorylation (OXPHOS) system. To maintain energy-consuming processes in OXPHOS deficient cells, alternative metabolic pathways are functionally coupled to the degradation, recycling and redistribution of biomolecules across distinct intracellular compartments. While transcriptional regulation of mitochondrial network expansion has been the focus of many studies, the molecular mechanisms promoting mitochondrial maintenance in energy-deprived cells remain poorly investigated. We performed transcriptomics, quantitative proteomics and lifespan assays to identify pathways that are mechanistically linked to mitochondrial network expansion and homeostasis in Caenorhabditis elegans lacking the mitochondrial calcium uptake protein 1 (MICU-1/MICU1). To support our findings, we carried out biochemical and image analyses in mammalian cells and mouse-derived tissues. We report that micu-1(null) mutations impair the OXPHOS system and promote C. elegans longevity through a transcriptional program that is independent of the mitochondrial calcium uniporter MCU-1/MCU and the essential MCU regulator EMRE-1/EMRE. We identify sphingosine phosphate lyase SPL-1/SGPL1 and the ATFS-1-target HOPS complex subunit VPS-39/VPS39 as critical lifespan modulators of micu-1(null) mutant animals. Cross-species investigation indicates that SGPL1 upregulation stimulates VPS39 recruitment to the mitochondria, thereby enhancing mitochondria-lysosome contacts. Consistently, VPS39 downregulation compromises mitochondrial network maintenance and basal autophagic flux in MICU1 deficient cells. In mouse-derived muscles, we show that VPS39 recruitment to the mitochondria may represent a common signature associated with altered OXPHOS system. Our findings reveal a previously unrecognized SGPL1/VPS39 axis that stimulates intracellular organelle interactions and sustains autophagy and mitochondrial homeostasis in OXPHOS deficient cells. [Display omitted] • micu-1(null) nematodes are long-lived mitochondrial mutants. • MICU-1/MICU1 deficiency stimulates VPS-39/VPS39 and SPL-1/SGPL1 upregulation. • VPS-39 sustains mitochondrial network expansion in micu-1(null) nematodes. • VPS39 and SGPL1 expression influences mitochondria-lysosome contact sites in MICU1 deficient cells. • VPS39/SGPL1 signaling may be a common signature of mitochondrial deficient cells. [ABSTRACT FROM AUTHOR]

Objective: To introduce the concept of patient competence and provide additional information on the concurrent validity of a new self-rating measure of patient competence in the context of cancer employing healthcare usage behaviors and more general self-rated features of patient competence as criteria. Methods: Based on a multi-center sample of n =536 patients with cancer, bivariate correlations and multiple regressions were computed. Results: The competence subscale of striving for autonomous decisions emerged as significant, albeit weak predictor of having used professional psycho-social support (r =.31, β =.28) and employing other complementary medicines (r =.28; B =.65) in relation to one's cancer. Problem-focused and emotion-focused competencies relate differently to different general features of self-rated competence like feeling informed and assertive or adapting well. Conclusion: Additional support for the concurrent validity of the new self-rating measure of patient competence in the context of cancer has been found. Viewed in perspective, this measure may therefore provide a methodological basis to examine determinants and health effects of patient competence empirically. Nevertheless, further research on the conceptualization and measurement of patient competence appears necessary. Practice implications: Having available measures of patients’ specific competencies in the context of cancer will help identify their strength and weaknesses in dealing with life-threatening disease and enhance their coping resources. [Copyright &y& Elsevier]

Abstract: Some neurodegenerative diseases including Alzheimer''s disease (AD) and amyotrophic lateral sclerosis (ALS) exhibit prominent defects in axonal transport. These defects can manifest as axonal swellings or spheroids, which correspond to axonal enlargements and aberrant accumulation of axonal cargoes, cytoskeletal proteins and lipids. Recently, a controversial scientific debate focussed on the issue whether Aβ serves as a trigger for aberrant axonal transport in the pathophysiology of AD. Prominent axonopathy has been shown to be induced by overexpression of proteins involved in several neurodegenerative diseases. Neurofilament, apolipoprotein E, Niemann-Pick protein and Tau transgenic mice with axonal trafficking deficits have been reported. Furthermore, motor deficits are frequently observed in patients with AD, which has been attributed to the typical tauopathy in post-mortem brain tissue. In the present report, we analyzed axonal neuropathology in the brain and spinal cord of a transgenic mouse model with abundant intraneuronal Aβ42 production and provide compelling evidence for axonal degeneration. The APP/PS1ki mice showed characteristic axonal swellings, spheroids, axonal demyelination and ovoids, which are myelin remnants of degenerated nerve fibers in an age-dependent manner. Abundant accumulation of intraneuronal N-modified Aβ, Thioflavin S-positive material and ubiquitin was found within the somatodendritic compartment of neurons. We conclude that the intraneuronal accumulation of Aβ-amyloid peptides is followed by axonal degeneration, and thus might be a causative factor for the axonal changes seen in AD. [Copyright &y& Elsevier]

The paper provides an overview on the 11th scientific conference of the European Society for Psycho-Oncology (ESPO), which took place in June 2001, at Heidelberg, Germany. The main topics discussed during the conference were: (1) the state of the art of research on the effects of psychological interventions in cancer patients; (2) psychosocial aspects in the new field of cancer genetics; (3) recent developments in Quality of Life research; (4) Psycho-Oncology from an European perspective; and (5) children and cancer. The conference gave an impressive picture of the many achievements Psycho-Oncology in Europe has accomplished during the last years, in the clinical and scientific domain. With recent biomedical innovations Psycho-Oncology is facing new challenges. Despite these achievements limitations have become apparent. Identifying these limitations, future aims can be outlined. Among these, there is the need for methodological refinement, as well as for proof of clinical relevance of research results, in order to narrow the gap between research and practice. [Copyright &y& Elsevier]

Background: Patients with the kyphoscoliotic type of Ehlers-Danlos syndrome have an increased risk of vascular complications such as aortic dissection and perforation. Cerebral ischemia has only rarely been documented.Patient Description: This 13-year-old girl with the kyphoscoliotic type of Ehlers-Danlos syndrome experienced a large right middle cerebral artery distribution infarction. Full intravenous heparinization was started in response to presumed arterial dissection. Magnetic resonance imaging studies including magnetic resonance angiography and digital subtraction angiography, however, did not confirm dissection but suggested with cerebral vasculitis extending from the intradural right internal carotid artery to the M2 branches of the middle cerebral artery. Combined steroid and cyclophosphamide therapy was associated with clinical improvement. Two months later she died from hemorrhagic shock caused by a two-sided spontaneous rupture of the aortic artery.Conclusions: Cerebral vasculitis should be included in the differential diagnosis of vascular complications in kyphoscoliotic type of Ehlers-Danlos syndrome. [ABSTRACT FROM AUTHOR]

• Regional differences in glial response at late phase after global hypoxia–ischemia. • Glassy large gemistocytes emerge upon removal of dead neurons in striate cortex. • CHI3L1+/GFAP+/S100β+ coexpressing gemistocytes in striate cortex, not in cerebellum. • Abundant IBA1+/CD68+/CHIT1+ macrophages at late posthypoxia phase in striate cortex. • CD68-/CHIT1-complex IBA1+ microglia at late posthypoxia phase in cerebellar cortex. Here, we studied the neuroinflammation- and ischemia-related glial markers chitotriosidase 1 (CHIT1) and chitinase-3-like protein 1 (CHI3L1, alias YKL-40) in the human striate cortex and cerebellum at different time points after global hypoxic-ischemic brain injury (HIBI). Both regions differ considerably in their glial cell population but are supplied by the posterior circulation. CHIT1 and CHI3L1 expression was compared to changes in microglial (IBA1, CD68), astrocytic (GFAP, S100β), and neuronal markers (H&E, neurofilament heavy chain, NfH; calretinin, CALR) using immunohistochemistry and multiple-label immunofluorescence. Initial striatal cortical and cerebellar Purkinje cell damage, detectable already 1/2 d after HIBI, led to delayed neuronal death, whereas loss of cerebellar NfH-positive stellate and CALR-positive granule cells was variable. During the first week post-HIBI, a transient reduction of IBA1-positive microglia was observed in both regions, and fragmented/clasmatodendritic cerebellar Bergmann glia appeared. In long-term survivors, both brain regions displayed high densities of activated IBA1-positive cells and CD68-positive macrophages, which showed CHIT1 co-localization in the striate cortex. Furthermore, enlarged GFAP- and S100β-positive astroglia emerged in both regions around 9–10 d post-HIBI, i.e., along with clearance of dead neurons from the neuropil, although GFAP-/S100β-positive gemistocytic astrocytes that co-expressed CHI3L1 were found only in the striate cortex. Thus, only GFAP-/S100β-positive astrocytes in the striate cortex, but not cerebellar Bergmann glia, differentiated into CHI3L1-positive gemistocytes. CHIT1 was co-expressed almost entirely in macrophages in the striate cortex and not cerebellum of long-term survivors, thereby indicating that CHIT1 and CHI3L1 could be valuable biomarkers for monitoring the outcome of global HIBI. [ABSTRACT FROM AUTHOR]

Abstract: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that plays a role in innate and adaptive immunity. Depending on the cellular context and disease state, MIF signaling is mediated by its receptors CXCR2, CXCR4 and/or CD74. Although it is known that MIF is endocytosed, the exact mechanism has remained unknown. In exploring the mechanism of MIF endocytosis with biologically active Alexa546MIF, pathway-specific inhibitors (monodansylcadaverine, MDC; chlorpromazine, CPZ; dynasore; dominant-negative dynamin, bafilomycin, nocodazole) and receptor overexpression and blockade approaches, we identified a clathrin/dynamin-dependent endocytosis pathway as the main track for MIF internalization. MIF endocytosis was rapid and colocalization with both early and late endosomal vesicles in a microtubule- and acidification-dependent manner was observed. LDL endocytosis (which is clathrin-mediated) served as a control and was similarly inhibited by MDC or dynasore. When MIF endocytosis was compared to that of transferrin, acetylated LDL, and choleratoxin B (the latter internalized by a clathrin-independent pathway) by colocalization studies, the MIF internalization pathway clearly resembled that of LDL but also shared early trafficking with transferrin, whereas no colocalization with choleratoxin was noted. To identify the receptors involved in MIF endocytosis, we focused on CD74 and CXCR4 which form a heteromeric complex. Ectopic overexpression of CD74 in HEK293 and HeLa cells, which do not endogenously express CD74, led to a marked acceleration of MIF endocytosis while pharmacological blockade of CXCR4, which is endogenously expressed on these cells, with AMD3100 led to a 20% reduction of MIF endocytosis in HEK293-CD74 transfectants, whereas in untransfected cells, a blockade of 40% was observed. Of note, both CD74 and CXCR4 strongly colocalize with Alexa546MIF both on the plasma membrane and in endosomal compartments. Moreover, MIF-stimulated AKT signaling, which was previously shown to involve both CD74 and CXCR4, was reduced by endocytosis inhibitors, indicating that MIF signaling is at least in part due to endosomal signaling mechanisms. Thus, MIF uptake follows a rapid LDL-like, clathrin- and dynamin-dependent endocytosis pathway, which is dependent on the receptors CD74 and CXCR4 and leads to the initiation of endosomal signaling responses. [Copyright &y& Elsevier]

Abstract: Neuroblastoma cell lines are commonly used as a model to study neuronal differentiation as they retain the capacity to differentiate into a neuronal-like phenotype. It is of great medical interest to understand the signalling pathways biasing differentiation versus proliferation. Neuroblastoma cells differentiate in response to serum reduction or addition of the cholesterol synthesis inhibitor mevastatin. The responsible pathways are not well characterized. In Neuro2a neuroblastoma cells, we found that mevastatin and serum withdrawal triggered the production of nitric oxide (NO). In addition, the differentiation of Neuro2a cells and the activation of Akt/PKB triggered by serum withdrawal could be blocked by addition of the NO synthetase (NOS) inhibitor l-NAME. Moreover, mevastatin and serum withdrawal rapidly increased the expression of the neuronal NOS isoform nNOS. However, addition of an NO donor SNP per se did not trigger neurite outgrowth. Taken together, we report for the first time a role of NO in neurite outgrowth of neuroblastoma cells triggered by mevastatin or serum reduction. [Copyright &y& Elsevier]

The invasive phenotype of glioblastoma multiforme (GBM) is a hallmark of malignant process, yet molecular mechanisms that dictate this locally invasive behavior remain poorly understood. Gene expression profiles of human glioma cells were assessed from laser capture-microdissected GBM cells collected from paired patient tumor cores and white matter-invading cell populations. Changes in gene expression in invading GBM cells were validated by quantitative reverse transcription polymerase chain reaction (QRT-PCR) and immunohistochemistry in an independent sample set. QRT-PCR confirmed the differential expression in 19 of 21 genes tested. Immunohistochemical analyses of autotaxin (ATX), ephrin B3, B-cell lymphoma-w (BCLW), and protein tyrosine kinase 2 beta showed them to be expressed in invasive glioma cells. The known GBM markers, insulin-like growth factor binding protein 2 and vimentin, were robustly expressed in the tumor core. A glioma invasion tissue microarray confirmed the expression of ATX and BCLW in invasive cells of tumors of various grades. GBM phenotypic and genotypic heterogeneity is well documented. In this study, we show an additional layer of complexity: transcriptional differences between cells of tumor core and invasive cells located in the brain parenchyma. Gene products supporting invasion may be novel targets for manipulation of brain tumor behavior with consequences on treatment outcome. [ABSTRACT FROM AUTHOR]

• Spinal motoneurons express NLRP1, NLRP3, NLRC4 AIM2 and the inflammasome adaptor ASC. • Immunoreactivity of AIM2 was detected in all types of glial cells. • Glial type-specific immunolabelling was observed for NLRP1 and NLRC4. • Increased NLRC4 is associated with pathogenesis in SOD1(G93A) mice and ALS patients. Inflammasomes are key components of the innate immune system and activation of these multiprotein platforms is a crucial event in the etiopathology of amyotrophic lateral sclerosis (ALS). Inflammasomes consist of a pattern recognition receptor (PRR), the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) and caspase 1. Exogenous or endogenous "danger signals" can trigger inflammasome assembly and promote maturation and release of pro-inflammatory cytokines, including interleukin 1β. Previous studies have demonstrated presence and activation of NLRP3 in spinal cord tissue from SOD1(G93A) mice and human sporadic ALS (sALS) patients. However, regulation and cell type-specific localization of other well-known PRRs has not yet been analysed in ALS. Here, we explored gene expression, protein concentration and cell type-specific localization of the NLRP1, NLRC4 and AIM2 inflammasomes in spinal cord samples from SOD1(G93A) mice and sALS patients. Transcription levels of NLRP1 and NLRC4, but not AIM2, were elevated in symptomatic SOD1(G93A) animals. Immunoblotting revealed elevated protein levels of NLRC4, which were significantly increased in sALS vs. control patients. Immunofluorescence studies revealed neuronal labelling of all investigated PRRs. Staining of AIM2 was detected in all types of glia, whereas glial type-specific labelling was observed for NLRP1 and NLRC4. Our findings revealed pathology-related and cell type-specific differences in the expression of subsets of PRRs. Besides NLRP3, NLRC4 appears to be linked more closely to ALS pathogenesis. [ABSTRACT FROM AUTHOR]

Objective: As satisfaction with information received is an important precondition of adherence to treatment in cancer patients, we aimed to examine the level of perceived information, information satisfaction and information needs, and examine the prospective association between information satisfaction and anxiety.Methods: In a multicenter study in Germany, 1398 cancer patients were evaluated in terms of this at baseline, after 6 and 12 months.Results: At baseline, the majority of patients reported to feel well-informed. Nevertheless, a considerable proportion reported to wish more information. The proportion of patients reporting unmet information needs declined over time (p < 0.001). Anxiety at baseline is negatively associated with information satisfaction after 6 months (β = -0.10, p < 0.01). Conversely, information satisfaction at baseline is negatively associated with anxiety after 6 months (β = -0.10, p < 0.01). At 12 months, only the negative path leading from anxiety to information satisfaction was significant (β = -0.12, p < 0.01).Conclusion: We found high levels of information received and high information satisfaction. Nevertheless, there was a considerable quantity of unmet information needs. A bidirectional relationship between information satisfaction and anxiety symptoms emerged after 6 months.Practice Implications: These results underline the priority of providing information and emotional support to cancer patients to improve satisfaction with information. [ABSTRACT FROM AUTHOR]

Objective Amino acid positron emission tomography (PET) using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) provides important additional information on the extent of viable tumor tissue of glioblastoma compared with magnetic resonance imaging (MRI). Especially after radiochemotherapy, progression of contrast enhancement in MRI is equivocal and may represent either tumor progression or treatment-related changes. Here, the first case comparing postmortem whole-brain histology of a patient with pretreated glioblastoma with dynamic in vivo FET PET and MRI is presented. Methods A 61-year-old patient with glioblastoma initially underwent partial tumor resection and died 11 weeks after completion of chemoradiation with concurrent temozolomide. Three days before the patient died, a follow-up FET PET and MRI scan indicated tumor progression. Autopsy was performed 48 hours after death. After formalin fixation, a 7-cm bihemispherical segment of the brain containing the entire tumor mass was cut into 3500 consecutive 20μm coronal sections. Representative sections were stained with hematoxylin and eosin stain, cresyl violet, and glial fibrillary acidic protein immunohistochemistry. An experienced neuropathologist identified areas of dense and diffuse neoplastic infiltration, astrogliosis, and necrosis. In vivo FET PET, MRI datasets, and postmortem histology were co-registered and compared by 3 experienced physicians. Results Increased uptake of FET in the area of equivocal contrast enhancement on MRI correlated very well with dense infiltration by vital tumor cells and showed tracer kinetics typical for malignant gliomas. An area of predominantly reactive astrogliosis showed only moderate uptake of FET and tracer kinetics usually observed in benign lesions. Conclusions This case report impressively documents the correct imaging of a progressive glioblastoma by FET PET. Highlights • This is the first study to compare modern neuroimaging techniques with postmortem whole-brain histology. • Amino acid PET using FET delineates vital tumor tissue in progressive glioblastoma. • FET PET tracer uptake kinetics might help differentiate between necrosis, reactive astrogliosis, and vital tumor cells. [ABSTRACT FROM AUTHOR]

Objective: We compared gynecological and breast cancer patients regarding their needs for information and psychosocial support, quality of life (QoL), and emotional distress and the relationship among these constructs.Methods: In a multicenter, cross-sectional study in Germany, we evaluated 1214 female cancer patients (317 with gynecological cancer, 897 with breast cancer). We obtained self-reports of unmet needs, using a self-developed measure. We measured QoL with the EORTC QLQ-C30, symptoms of depression with the Patient Health Questionnaire (PHQ-9), and symptoms of anxiety with the Generalized Anxiety Disorder Scale (GAD-7).Results: Compared to breast cancer patients, gynecological cancer patients felt less informed about several aspects of their disease, particularly regarding psychological support (p<0.001), tended to have more unmet information needs, and reported lower QoL levels. Lower emotional functioning, but higher physical functioning were independent correlates of the level of unmet information needs. Depressive symptoms and higher physical functioning (only in breast cancer) were independent correlates of higher needs for psychosocial support.Conclusion: Compared to breast cancer, gynecological cancer patients were less satisfied with the information received and reported lower levels of QoL.Practice Implications: Both clinicians and policy makers should take efforts to address the higher needs of gynecological cancer patients. [ABSTRACT FROM AUTHOR]

Background: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) has been increasingly acknowledged to be an initial specific manifestation of alpha-synucleinopathies such as Parkinson's disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). Recent findings suggest that cutaneous abnormalities like small fiber neuropathy and alpha-synuclein deposition might reflect brain pathology and might function as early biomarkers in PD. This is the first study to elucidate whether iRBD patients already suffer from distinctive cutaneous features.Methods: We examined skin punch biopsies from the distal leg of 18 iRBD patients and 22 age- and sex-matched controls using immunohistochemistry and microscopy. Further clinical evaluation included structured interviews, clinical motor and non-motor questionnaires and rating scales (e.g. Unified Parkinson's disease rating scale [UPDRS], non-motor symptoms questionnaire [NMS-Quest] and Beck Depression Inventory, Epworth Sleepiness Scale, evaluation of cognitive and olfactory functioning as well as blood samples.Results: Intraepidermal nerve fiber density (IEFND) was reduced in iRBD patients compared to controls (p = 0.037), whereas the axon swelling ratio did not differ between groups. Patients with iRBD reported non-motor symptoms more frequently than controls (UPDRS I, NMS-Quest). Olfaction and daytime sleepiness differed between both groups, whereas there were no differences regarding cognition.Conclusions: These in vivo findings demonstrate small fiber neuropathy in iRBD patients that are associated with non-motor symptoms indicating that peripheral abnormalities may occur early in iRBD. However, the prognostic value has to be further investigated in longitudinal studies. [ABSTRACT FROM AUTHOR]

Background Cancer incidence increases exponentially with advancing age, cancer patients live longer than in the past, and many new treatments focus on stabilizing disease and HRQOL. The objective of this study is to examine how cancer affects patients' HRQOL and whether their HRQOL is age-dependent. Methods Data from 25 EORTC randomized controlled trials was pooled. EORTC QLQ-C30 mean scores for the cancer cohort and five general population cohorts were compared to assess the impact of cancer on patients' HRQOL. Within the cancer cohort, multiple linear regressions (two-sided level P-value = 0.05 adjusted for multiple testing.) were used to investigate the association between age and HRQOL, adjusted for gender, WHO performance status (PS), distant metastasis and stratified by cancer site. A difference of 10 points on the 0–100 scale was considered clinically important. Results Cancer patients generally have worse HRQOL compared to the general population, but the specific HRQOL domains impaired vary with age. When comparing the cancer versus the general population, young cancer patients had worse financial problems, social and role functioning, while the older cancer groups had more appetite loss. Within the cancer cohort, HRQOL was worse with increasing age for physical functioning and constipation, and better with increasing age for social functioning, insomnia and financial problems (all p < 0.05). Conclusion HRQOL is impaired in cancer patients compared to the general population, but the impact on specific HRQOL domains varies by age. Within the cancer population, some HRQOL components improve with age while others deteriorate. Optimal care for older cancer patients should target HRQOL domains most relevant to this population. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Argon at a dosage of 70% is neuroprotective when given 1h after cardiac arrest (CA) in rats. In a rodent model, we investigated if the neuroprotective effects of argon are dose dependent and mediated by adenosine triphosphate dependent potassium (KATP) channels. Methods: Forty-seven male Sprague-Dawley rats were subjected to 7min of CA and 3min of cardiopulmonary resuscitation (CPR). In protocol I animals were randomized to receive either 70% or 40% argon ventilation 1h after successful CPR or no argon-treatment. Animals of the second protocol also received 1h of 70% argon ventilation or no argon treatment but were randomized to a group receiving the KATP channel blocker 5-hydroxydecanoate (5-HD). For all animals a neurological deficit score (NDS) was calculated daily for seven days following the experiment before the animals were killed and the brains harvested for histopathological analyses. Results: All animals survived. Control animals exhibited severe neurologic dysfunction at all points in time as measured with the NDS. Argon treated animals showed significant improvements in the NDS through all postoperative days in a dose dependent fashion. This was paralleled by a significant reduction in the neuronal damage index in the neocortex and the hippocampal CA 3/4 region. Administration of 5-HD neither abolished the positive effects on functional recovery nor on histopathologic changes observed in the argon group. Conclusion: Our study demonstrates a dose dependent neuroprotective effect of argon administration in this rodent model, which is not mediated via ATP dependent potassium channels. [Copyright &y& Elsevier]

Abstract: Numerous in-vitro techniques exist for investigating the influence of 3D substrate topography on sensory axon growth. However, simple and cost-effective methods for studying post-natal motor axon interactions with such substrates are lacking. Here, spinal cord organotypic slice cultures (OSC) from post-natal day 7–9 rat pups were presented with spinal nerve roots, or blocks of fibrin hydrogel or 3D microporous collagen scaffolds to investigate motor axon–substrate interactions. By 7–14 days, axons from motor neuronal pools extended into the explanted nerve roots, growing along Schwann cell processes and demonstrating a full range of axon-Schwann cell interactions, from simple ensheathment to concentric wrapping by Schwann cell processes and the formation of compact myelin within a basal lamina sheath. Extensive motor axon regeneration and all stages of axon-Schwann interactions were also supported within the longitudinally orientated microporous framework of the 3D collagen scaffold. In stark contrast, the simple fibrin hydrogel only supported axon growth and cell migration over its surface. The relative ease of demonstrating such motor axon regeneration through the microporous 3D framework by immunofluorescence, two-photon microscopy and transmission electron microscopy strongly supports the adoption of this technique for assaying the influence of substrate topography and functionalization in regenerative bioengineering. [Copyright &y& Elsevier]

Overexpression of the epidermal growth factor receptor (EGFR) is observed in a large number of neoplasms. The monoclonal antibody cetuximab/Erbitux is frequently applied to treat EGFR-expressing tumors. However, the application of cetuximab alone or in combination with radio- and/or chemotherapy often yields only little benefit for patients. In the present study, we describe a mechanism that explains resistance of both tumor cell lines and cultured primary human glioma cells to cetuximab. Treatment of these cells with cetuximab promoted DNA synthesis in the absence of increased proliferation, suggesting that DNA repair pathways were activated. Indeed, we observed that cetuximab promoted the activation of the DNA damage response pathway and prevented the degradation of essential meiotic endonuclease 1 homolog 1 (Eme1), a heterodimeric endonuclease involved in DNA repair. The increased levels of Eme1 were necessary for enhanced DNA repair, and the knockdown of Eme1 was sufficient to prevent efficient DNA repair in response to ultraviolet-C light or megavoltage irradiation. These treatments reduced the survival of tumor cells, an effect that was reversed by cetuximab application. Again, this protection was dependent on Eme1. Taken together, these results suggest that cetuximab initiates pathways that result in the stabilization of Eme1, thereby resulting in enhanced DNA repair. Accordingly, cetuximab enhances DNA repair, reducing the effectiveness of DNA-damaging therapies. This aspect should be considered when using cetuximab as an antitumor agent and suggests that Eme1 is a negative predictive marker. [ABSTRACT FROM AUTHOR]

Background: Neurofilament light chain (NF-L) is the major intermediate filament specifically expressed in neurons and their axons. No data are available concerning serum levels of NF-L after global cerebral ischemia due to cardiac arrest. To find a specific neuronal marker of long-term neurological outcome, we examined serum levels of NF-L in patients after cardiac arrest. Methods: A prospective observational cohort study was conducted. Blood samples for the measurement of NF-L were analyzed from 85 patients within 2h after admission, as well as on 2nd, 3rd, 5th, and 7th day. Neurological outcome was assessed 6months after cardiac arrest by employing the Modified Glasgow Outcome Score (MGOS). Results: The serum course of NF-L in patients with poor neurological outcome (MGOS 1+2) was significantly augmented compared to patients with good neurological outcome (MGOS 3+4+5) (on admission (pg/ml): good: 125±11.7 vs. poor: 884.4±86.2pg/ml; 3rd day: good: 153.1±13.2 vs. poor: 854.4±119.1; 7th day: good: 112.5±10.4 vs. poor: 1011.8±100.8; P <0.001). Intermediate NF-L serum values were found in patients with MGOS 0, which represents a mixture of patients who died with and without certified brain damage (on admission (pg/dl): 433.7±49.8; 3rd day: 598.3±86.6; 7th day: 474±77.4). A prediction power of 0.93 (c-statistic, 95%-CI 0.87–0.99) on 1st, 0.85 (0.81–0.95) on 2nd, 0.92 (0.85–0.99) on 3rd, 0.97 (0.92–1) on 5th and 0.99 (0.98–1) on 7th day was achieved for NF-L predicting poor neurological outcome. Conclusions: The present data suggest that within 7days after cardiac arrest serum NF-L is a valuable marker of long-term neurological outcome. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Assessment of oral and dental problems is seldom routine in clinical oncology, despite the potential negative impact of these problems on nutritional status, social function and quality of life (QoL). The aim was to develop a supplementary module to the European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) focusing on oral health and related QoL issues in all cancer diagnoses. Methods: The module development followed the EORTC guidelines. Phases 1&2 were conducted in France, Germany, Greece, Netherlands, Norway and United Kingdom, while seven countries representing seven languages were included in Phase 3. Results: Eighty-five QoL-items were identified from systematic literature searches. Semi-structured interviews with health-care professionals experienced in oncology and oral/dental care (n =18) and patients (n =133) resulted in a provisional module with 41 items. In phase 3 this was further tested in 178 European patients representing different phases of disease and treatment. Results from the interviews, clinical experiences and statistical analyses resulted in the EORTC QLQ-OH17. The module consists of 17 items conceptualised into four multi-item scales (pain/discomfort, xerostomia, eating, information) and three single items related to use of dentures and future worries. Conclusion: This study provides a useful tool intended for use in conjunction with the EORTC QLQ-C30 for assessment of oral and dental problems. The increased awareness may lead to proper interventions, thereby preventing more serious problems and negative impact on QoL. The reliability and validity, the cross-cultural applicability and the psychometric properties of the module will be tested in a larger international study. [Copyright &y& Elsevier]

Abstract: The use of bioengineered nerve guides as alternatives for autologous nerve transplantation (ANT) is a promising strategy for the repair of peripheral nerve defects. In the present investigation, we present a collagen-based micro-structured nerve guide (Perimaix) for the repair of 2 cm rat sciatic nerve defects. Perimaix is an open-porous biodegradable nerve guide containing continuous, longitudinally orientated channels for orientated nerve growth. The effects of these nerve guides on axon regeneration by six weeks after implantation have been compared with those of ANT. Investigation of the regenerated sciatic nerve indicated that Perimaix strongly supported directed axon regeneration. When seeded with cultivated rat Schwann cells (SC), the Perimaix nerve guide was found to be almost as supportive of axon regeneration as ANT. The use of SC from transgenic green-fluorescent-protein (GFP) rats allowed us to detect the viability of donor SC at 1 week and 6 weeks after transplantation. The GFP-positive SC were aligned in a columnar fashion within the longitudinally orientated micro-channels. This cellular arrangement was not only observed prior to implantation, but also at one week and 6 weeks after implantation. It may be concluded that Perimaix nerve guides hold great promise for the repair of peripheral nerve defects. [Copyright &y& Elsevier]

Abstract: An irregular ventricular response during atrial fibrillation (AF) has been shown to mediate an increase in sympathetic nerve activity in human subjects. The molecular mechanisms remain unclear. This study aimed to investigate the impact of rate and irregularity on nerve growth factor (NGF) expression in cardiomyocytes, since NGF is known to be the main contributor to cardiac sympathetic innervation density. Cell cultures of neonatal rat ventricular myocytes were electrically stimulated for 48h with increasing rates (0, 5 and 50Hz) and irregularity (standard deviation (SD)=5%, 25% and 50% of mean cycle length). Furthermore, we analyzed the calcineurin-NFAT and the endothelin-1 signalling pathways as possible contributors to NGF regulation during arrhythmic stimulation. We found that the increase of NGF expression reached its maximum at the irregularity of 25% SD by 5Hz (NGF: 5Hz 0% SD=1 vs. 5Hz 25% SD=1.57, P <0.05). Specific blockade of the ET-A receptor by BQ123 could abolish this NGF increase (NGF: 5Hz 25% SD+BQ123=0.66, P <0.05). High frequency electrical field stimulation (HFES) with 50Hz decreased the NGF expression in a significant manner (NGF: 50Hz=0.55, P <0.05). Inhibition of calcineurin-NFAT signalling with cyclosporine-A or 11R-VIVIT abolished the HFES induced NGF down-regulation (NGF: 50Hz+CsA=1.14, P <0.05). In summary, this study reveals different signalling routes of NGF expression in cardiomyocytes exposed to increasing rates and irregularity. Whether this translates into different degrees of NGF expression and possibly neural sympathetic growth in various forms of ventricular rate control during AF remains to be elucidated in further studies. [Copyright &y& Elsevier]

Abstract: Purpose: Previous data indicate that 100% O2 ventilation during early reperfusion after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) increases neuronal death. However, current guidelines encourage the use of 100% O2 during resuscitation and for an undefined period thereafter. We retrospectively analyzed data from a porcine CA model and hypothesized that prolonged hyperoxic reperfusion would be associated with increased neurohistopathological damage and impaired neurological recovery. Methods: Fifteen male pigs underwent 8min of CA and 5min of CPR. After resuscitation animals were ventilated with either 100% oxygen for 60min (hyperoxia; n =8) or 10min (normoxia; n =7). Physiological variables were obtained at baseline and 10, 60 and 240min after resuscitation. Daily functional performance was assessed using an established neurocognitive test in parallel to a neurological deficit score (NDS). On day 5, brains of the re-anaesthetized pigs were harvested for neurohistopathological analyses. Results: At baseline there were no differences in hemodynamics and neurological status between groups. Post-arrest only PaO2, as a result of the different inspired oxygen fractions, was significantly higher in the hyperoxia group. There was a numerical trend towards improved clinical recovery in both the NDS and the neurocognitive testing for animals exposed to 10min of 100% oxygen. However, hyperoxic animals showed a significantly greater degree of necrotic neurons and perivascular inflammation in the striatum in comparison to normoxic animals. Conclusion: In this retrospective analysis prolonged hyperoxia after CA aggravated necrotic brain damage and perivascular inflammation in the striatum of pigs. [ABSTRACT FROM AUTHOR]

Abstract: Peripheral nerve injuries that induce gaps larger than 1–2cm require bridging strategies for repair. Autologous nerve grafts are still the gold standard for such interventions, although alternative treatments, as well as treatments to improve the therapeutic efficacy of autologous nerve grafting are generating increasing interest. Investigations are still mostly experimental, although some clinical studies have been undertaken. In this review, we aim to describe the developments in bridging technology which aim to replace the autograft. A multi-disciplinary approach is of utmost importance to develop and optimise treatments of the most challenging peripheral nerve injuries. [ABSTRACT FROM AUTHOR]

Abstract: Background: Xenon (Xe) is neuroprotective when given 1h after cardiopulmonary resuscitation (CPR). Here, we investigated if an earlier administration of Xe or isoflurane (Iso) would also reduce neurological dysfunction. Methods: 10min after CPR from 8min of cardiac arrest 21 pigs were randomized to three groups (n =7/group) and then ventilated for 1h with gas mixtures as follows: (1) control: 30% O2 +70% N2; (2) Iso: 30% O2 +69% N2 +1% Iso; (3) Xe: 30% O2 +70% Xe. Physiological variables were obtained before cardiac arrest and 10, 60 and 240min post-CPR including cardiac output (CO) and mean arterial pressure (MAP). Four days after CPR we assessed functional performance using an established neurocognitive test and overall neurological status using a neurologic deficit score (NDS). On day 5, brains of the re-anaesthetized pigs were harvested for neurohistopathological analyses. Results: Prior to CPR there were no differences in hemodynamics and neurological status between groups. CO and MAP were significantly reduced after starting Iso administration. Both variables were also significantly lower in comparison to Xe and control animals. Control animals presented severe neurological dysfunction as measured by the NDS and the neurocognitive tests. Although Xe and Iso animals showed slightly better functional outcome this trend was not significant. Histopathological evaluation revealed ischaemic damage of neurons predominantly in the CA1 sector of the hippocampus with no differences between groups. Conclusions: In this study early administration of Xe and Iso did not significantly reduce neurological dysfunction and histopathological alterations induced by cardiac arrest and CPR. [Copyright &y& Elsevier]

Abstract: Therapeutic benefits of autologous nerve grafting in repair of peripheral nerve lesions have not been reached using any alternative nerve guide. Nevertheless, issues of co-morbidity and limited availability of donor nerves urgently ask for a need of bioartificial nerve guides which could either replace or complement autologous nerve grafts. It is increasingly appreciated that optimal nerve guides comprise both physical and molecular cues in support of peripheral axon regeneration. Now, we present a collagen-based microstructured 3D nerve guide containing numerous longitudinal guidance channels with dimensions resembling natural endoneurial tubes. Moreover, these nerve guides could be functionalized by Schwann cell (SC) seeding. Viable SCs did not only adhere to the nerve guide, but also migrated throughout the guidance channels. Of particular importance was the observation that SCs within the guidance channels formed cellular columns reminiscent of “Bands of Büngner”, which are crucial structures in the natural process of peripheral nerve regeneration during the Wallerian degeneration. We, therefore, conclude that our orientated 3D nerve guides (decorated with SCs) with their physical and molecular properties may hold great promise in the repair of peripheral nerve lesion and serve as a basis for future experimental regeneration studies. [Copyright &y& Elsevier]