ABSTRACT
Background: Inpatient treatment (IT) is the predominant form of psychiatric care in Germany and worldwide, whereby forms of psychiatric treatment have mainly evolved in the direction of home services. Inpatient equivalent home treatment (IEHT) is a new and additional pillar of psychiatric acute care provision legally embedded since 2018 in Germany. Objective: The aim of this study was to conduct an in-depth exploration as little qualitative research has been performed so far in Germany to examine possible differences in patient satisfaction with IT compared with IEHT. Methods: In the current qualitative study, N = 9 patients of a German hospital providing IT and IEHT were interviewed with the problem-centered interview. Inclusion criteria were IT or IT with subsequent IEHT. The theoretical sampling method was applied to select test persons in the research process. The experiences of the participants during their psychiatric treatment were analyzed using a qualitative content analysis. Results: The results of both types of psychiatric treatment refer to different satisfaction factors during the treatment period. The function of fellow patients, the setting of the treatment, the conditions in place, and the relationship to relatives turn out to be pivotal for patient satisfaction. In addition, the quality of the therapy and relationship to caregivers itself can have an impact on patient satisfaction, particularly by shared decision making. During the IEHT, patient satisfaction can be strengthened by the possibility to handle daily tasks, to be close to relatives, while not so close to fellow patients, whereas IT patients are mostly satisfied because of the distance to their everyday life and the closeness to fellow patients. The choice of the form of psychiatric treatment according to the individual needs of the patients seems to be one key driver that can in turn increase patient satisfaction. In addition, a clean and hygienic environment seems to be critical for our respondents as a lack of it is one of the reasons to drop out of treatment. Conclusions: Despite its limitations, this hypothesis-generating study is one of the first investigating German IEHT in comparison with IT in an in-depth qualitative approach contributing to a patient-oriented and cost-effective psychiatric treatment. Although hospitals are highly complex organizations and therefore not directly comparable, other German and international providers of IEHT may derive several generic success factors from this study for the development and improvement of patient satisfaction.
ABSTRACT
Placebo (PE) and nocebo effects (NE) have been subjects of systematic research in medicine and psychotherapy for many decades to distinguish between the (specific) pharmacological effect of medication and the (unspecific) effect of the context. Despite this significant research, the awareness, operationalisation, and reflection of the multiplicity of PE, NE, and psychosocial context effects (PSCE) is currently limited when researching outcomes of diet changes in studies without randomisation and placebo control. This neglection is critical as it could systematically influence outcomes by moderating and mediating them and thus reducing the validity and evidence base of these studies. Therefore, we performed a (non-systematic) narrative review (NR) on the following objectives: (1) present a concise overview about the relevance of PE, NE, and PSCE in medicine and nutrition research; (2) review the current state of research on reflecting context effects when studying diet changes; (3) provide useful theoretical foundations via consideration and integration of micro- and macro context effects; (4) operationalise as hypotheses the potential PE, NE, and PSCE which are specific for researching diet changes; and (5) derive their impact for future research as well as for nutrition counselling. The electronic search in this NR for objective (2) identified N = 5 publications and for objective (4) we found N = 61 articles retrieved in the first round of search, additional references were identified by a manual and snowball search among the cited references resulting finally in N = 37. This NR offers a synoptical basis to foster awareness and operationalisation of a variety of PE, NE, and PSCE. Interdisciplinary research teams should monitor these factors using, e.g., qualitative, mixed-method studies, process evaluation, item bank approaches, moderator and mediator analysis that might reveal substantially new insights, and outcomes of relevance to science and nutrition counselling. Nevertheless, the present NR has several limitations, especially as it is non-systematic, because it is a very heterogeneous field of research, in which the topic we are investigating is usually regarded as marginal and subordinate. Therefore, future research should conduct systematic reviews and particularly theory-based primary studies (experimental research) on hypotheses of PE, NE, and PSCE in outcome research in diet changes.
ABSTRACT
Unilateral brain injury is known to disrupt the balance between the two cortices, as evidenced by an abnormally high interhemispheric inhibitory drive from motor cortex M1intact to M1lesioned transmitted transcallosally. Our previous work has shown that the deletion of homeobox gene Emx1 not only led to the agenesis of the corpus callosum (cc), but also to reduced hippocampal neurogenesis. The current study sought to determine whether lacking the cc affected the recovery of forelimb function and hippocampal plasticity following training of the affected limb in mice with unilateral traumatic brain injuries (TBI). One week after TBI, produced by a controlled cortical impact to impair the preferred limb, Emx1 wild type (WT) and knock out (KO) mice were subjected to the single-pellet reaching task with the affected limb for 4 weeks. Both TBI and Emx1 deletion had overall adverse effects on the successful rate of reaching. However, TBI significantly affected reaching performance only in the WT mice and not in the KO mice. Both TBI and Emx1 gene deletion also negatively affected hippocampal neurogenesis, demonstrated by a reduction in doublecortin (DCX)-expressing immature neurons, while limb training enhanced DCX expression. However, limb training increased DCX cells in KO mice only in the TBI-treated group, whereas it induced neurogenesis in both WT mice groups regardless of the treatment. Our finding also suggests that limb training enhances neuroplasticity after brain injury at functionally remote regions including the hippocampus, which may have implications for promoting overall recovery of function after TBI.
Subject(s)
Agenesis of Corpus Callosum/complications , Brain Injuries, Traumatic/complications , Brain Injuries, Traumatic/rehabilitation , Forelimb/physiopathology , Hippocampus/physiopathology , Neurogenesis , Agenesis of Corpus Callosum/pathology , Agenesis of Corpus Callosum/physiopathology , Animals , Brain Injuries, Traumatic/pathology , Brain Injuries, Traumatic/physiopathology , Disease Models, Animal , Doublecortin Protein , Hippocampus/pathology , Homeodomain Proteins/genetics , Male , Mice, Knockout , Motor Skills/physiology , Neurogenesis/physiology , Neurological Rehabilitation , Neuronal Plasticity/physiology , Random Allocation , Transcription Factors/deficiency , Transcription Factors/geneticsABSTRACT
In cancer care, where patients and their families experience significant emotional distress and patients have to deal with complex medical information, patient centeredness is an important aspect of quality of care. The aim of this study is to examine the impact of patients' trust in their oncologists and patients' enablement on changes in health-related quality of life of colon cancer patients during follow-up care. We conducted a prospective study in a representative sample of private practices of German oncologists (N = 44). Patients (N = 131) filled out a standardized questionnaire prior to their first consultation (T0), directly after the first consultation (T1) and after two months (T2). Data were analyzed by structural equation modeling. Significant associations were found between trust in physician and changes in physical functioning between T1 and T2, and between trust in physician and patient enablement. Patient enablement is significantly associated with changes in physical functioning between T1 and T2. The results underline the importance of building a close and trustful patient-physician relationship in the oncology encounter. A central mechanism of the association between the quality of the relationship and health outcomes seems to be patient enablement. To enable patients to cope with their situation by making them understand their diagnosis, treatments, and side effects can impact health-related quality of life in physical domains.
Subject(s)
Colonic Neoplasms/therapy , Oncologists/statistics & numerical data , Physician-Patient Relations , Quality of Life , Trust , Adaptation, Psychological , Female , Germany , Humans , Male , Medical Oncology , Middle Aged , Prospective Studies , Surveys and QuestionnairesABSTRACT
Hematologists and oncologists in private practice play a central role in the care provided for cancer patients. The present study analyzes stress and relaxation aspects in the work of hematologists and oncologists in private practice in Germany in relation to emotional exhaustion, as a core dimension of burnout syndrome. The study focuses on the opportunities for internal recovery using breaks and time out during the working day, the frequency of working on weekends and on vacation, and the physician's work-home and home-work conflict. Postulated associations between the constructs were analyzed using a structural equation model. If work leads to conflicts in private life (work-home conflict), it is associated with greater emotional exhaustion. Working frequently at the weekend is associated with greater work-home conflict and indirectly with greater emotional exhaustion. By contrast, the availability of opportunities to relax and recover during the working day is associated with less work-home conflict and indirectly with less emotional exhaustion. These results underline the importance of internal recovery opportunities during the working day and a successful interplay between working and private life for the health of outpatient hematologists and oncologists.
Subject(s)
Burnout, Professional/epidemiology , Compassion Fatigue/epidemiology , Hematology/statistics & numerical data , Medical Oncology/statistics & numerical data , Physicians/statistics & numerical data , Private Practice/statistics & numerical data , Work-Life Balance/statistics & numerical data , Adult , Female , Germany/epidemiology , Humans , Male , Middle Aged , Oncologists/statistics & numerical dataABSTRACT
Emx1 has long been implicated in embryonic brain development. Previously we found that mice null of Emx1 gene had smaller dentate gyri and reduced neurogenesis, although the molecular mechanisms underlying this defect was not well understood. To decipher the role of Emx1 gene in neural regeneration and the timing of its involvement, we determine the frequency of neural stem cells (NSCs) in embryonic and adult forebrains of Emx1 wild type (WT) and knock out (KO) mice in the neurosphere assay. Emx1 gene deletion reduced the frequency and self-renewal capacity of NSCs of the embryonic brain but did not affect neuronal or glial differentiation. Emx1 KO NSCs also exhibited a reduced migratory capacity in response to serum or vascular endothelial growth factor (VEGF) in the Boyden chamber migration assay compared to their WT counterparts. A thorough comparison between NSC lysates from Emx1 WT and KO mice utilizing 2D-PAGE coupled with tandem mass spectrometry revealed 38 proteins differentially expressed between genotypes, including the F-actin depolymerization factor Cofilin. A global systems biology and cluster analysis identified several potential mechanisms and cellular pathways implicated in altered neurogenesis, all involving Cofilin1. Protein interaction network maps with functional enrichment analysis further indicated that the differentially expressed proteins participated in neural-specific functions including brain development, axonal guidance, synaptic transmission, neurogenesis, and hippocampal morphology, with VEGF as the upstream regulator intertwined with Cofilin1 and Emx1. Functional validation analysis indicated that apart from the overall reduced level of phosphorylated Cofilin1 (p-Cofilin1) in the Emx1 KO NSCs compared to WT NSCs as demonstrated in the western blot analysis, VEGF was able to induce more Cofilin1 phosphorylation and FLK expression only in the latter. Our results suggest that a defect in Cofilin1 phosphorylation induced by VEGF or other growth factors might contribute to the reduced neurogenesis in the Emx1 null mice during brain development.
ABSTRACT
Hypusine modification of the eukaryotic initiation factor 5A (eIF-5A) is emerging as a crucial regulator in cancer, infections, and inflammation. Although its contribution in translational regulation of proline repeat-rich proteins has been sufficiently demonstrated, its biological role in higher eukaryotes remains poorly understood. To establish the hypusine modification system as a novel platform for therapeutic strategies, we aimed to investigate its functional relevance in mammals by generating and using a range of new knock-out mouse models for the hypusine-modifying enzymes deoxyhypusine synthase and deoxyhypusine hydroxylase as well as for the cancer-related isoform eIF-5A2. We discovered that homozygous depletion of deoxyhypusine synthase and/or deoxyhypusine hydroxylase causes lethality in adult mice with different penetrance compared with haploinsufficiency. Network-based bioinformatic analysis of proline repeat-rich proteins, which are putative eIF-5A targets, revealed that these proteins are organized in highly connected protein-protein interaction networks. Hypusine-dependent translational control of essential proteins (hubs) and protein complexes inside these networks might explain the lethal phenotype observed after deletion of hypusine-modifying enzymes. Remarkably, our results also demonstrate that the cancer-associated isoform eIF-5A2 is dispensable for normal development and viability. Together, our results provide the first genetic evidence that the hypusine modification in eIF-5A is crucial for homeostasis in mammals. Moreover, these findings highlight functional diversity of the hypusine system compared with lower eukaryotes and indicate eIF-5A2 as a valuable and safe target for therapeutic intervention in cancer.
Subject(s)
Lysine/analogs & derivatives , Mixed Function Oxygenases/genetics , Oxidoreductases Acting on CH-NH Group Donors/genetics , Peptide Initiation Factors/metabolism , Animals , Homeostasis/genetics , Humans , Lysine/genetics , Lysine/metabolism , Mice , Mice, Knockout , Mixed Function Oxygenases/metabolism , Neoplasms/genetics , Neoplasms/pathology , Oxidoreductases Acting on CH-NH Group Donors/metabolism , Peptide Initiation Factors/genetics , Protein Biosynthesis , Protein Interaction Maps , Protein Processing, Post-TranslationalABSTRACT
miR-29 is expressed strongly in the brain and alterations in expression have been linked to several neurological disorders. To further explore the function of this miRNA in the brain, we generated miR-29a/b-1 knockout animals. Knockout mice develop a progressive disorder characterized by locomotor impairment and ataxia. The different members of the miR-29 family are strongly expressed in neurons of the olfactory bulb, the hippocampus and in the Purkinje cells of the cerebellum. Morphological analysis showed that Purkinje cells are smaller and display less dendritic arborisation compared to their wildtype littermates. In addition, a decreased number of parallel fibers form synapses on the Purkinje cells. We identified several mRNAs significantly up-regulated in the absence of the miR-29a/b-1 cluster. At the protein level, however, the voltage-gated potassium channel Kcnc3 (Kv3.3) was significantly up-regulated in the cerebella of the miR-29a/b knockout mice. Dysregulation of KCNC3 expression may contribute to the ataxic phenotype.
Subject(s)
Ataxia/metabolism , Cerebellum/metabolism , MicroRNAs/metabolism , Purkinje Cells/metabolism , Shaw Potassium Channels/metabolism , Animals , Behavior, Animal , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor ActivityABSTRACT
PURPOSE: A common phenomenon among cancer patients is a fear of cancer recurrence or cancer progression (FOP). The aim of the present study was to analyze whether the oncologist is able to reduce patients' FOP at the initial clinical interview. METHOD: A prospective, longitudinal study included patients who were consulting private-practice oncologists in Germany for the first time. Recruitment was carried out by 44 members of the Professional Organization of Office-Based Hematologists and Oncologists. In the patient surveys, data on colon cancer patients' perceptions of communications with their oncologist and on patient-reported outcomes were collected over a period of 6 months. The present study analyzed the patients' data before their first consultation (T 0) and within 3 days after the first consultation (T 1). RESULTS: A total of 169 patients agreed to participate in the study. Backwards multiple regression analysis was conducted to determine whether the change (T 0-T 1) in FOP is associated with demographic, medical, or psychosocial determinants, or with the physician-patient communication. A significant association was found between the change in FOP and interruptions to the conversation, the comprehensibility of the information provided, the extent of perceived empathy from the physician, and the patient's social support and family status. CONCLUSION: Private social support and the initial medical encounter can help reduce FOP. Particularly, oncologists should ensure that they facilitate the presentation of information in a comprehensible way while avoiding interruptions and that they take particular care of patients with poor social support.
Subject(s)
Fear , Neoplasm Recurrence, Local/psychology , Neoplasms/psychology , Physician-Patient Relations , Practice Patterns, Physicians'/organization & administration , Survivors/psychology , Adult , Aged , Fear/psychology , Female , Germany , Humans , Longitudinal Studies , Male , Middle Aged , Patient Satisfaction , Prospective Studies , Referral and Consultation , Social SupportABSTRACT
STUDY AIM: Physician empathy constitutes an outcome-relevant aim of medical education. Yet, the factors promoting and inhibiting physician empathy have not yet been extensively researched, especially in Germany. In this study, we explored German medical students' views of the factors promoting and inhibiting their empathy and how their experiences were related to their curricula. METHODS: A qualitative short survey was conducted at three medical schools: Bochum University, the University of Cologne and Witten/Herdecke University. Students were invited to complete an anonymous written questionnaire comprised of open-ended questions inquiring about the educational content of and situations during their medical education that positively or negatively impacted their empathy. Data were analyzed through qualitative content analysis according to the methods of Green and Thorogood. RESULTS: A total of 115 students participated in the survey. Respondents reported that practice-based education involving patient contact and teaching with reference to clinical practice and the patient's perspective improved their empathy, while a lack of these inhibited it. Students' internal reactions to patients, such as liking or disliking a patient, prejudice and other attitudes, were also considered to influence their empathy. Although each of the three schools takes a different approach to teaching interpersonal skills, no relevant differences were found in their students' responses concerning the possible determinants of empathy. CONCLUSION: Providing more training in practice and more contact with patients may be effective ways of promoting student empathy. Students need support in establishing therapeutic relationships with patients and in dealing with their own feelings and attitudes. Such support could be provided in the form of reflective practice training in order to promote self-awareness. More research is needed to evaluate these hypothetical conclusions.
Subject(s)
Awareness , Education, Medical, Undergraduate , Empathy , Physician-Patient Relations , Self-Assessment , Adult , Attitude of Health Personnel , Communication , Female , Germany , Humans , Male , Outcome and Process Assessment, Health Care , Qualitative Research , Schools, Medical , Surveys and Questionnaires , Young AdultABSTRACT
Central aspects in the pathogenesis of scrub typhus, an infection caused by Orientia (O.) tsutsugamushi, have remained obscure. Its organ and cellular tropism are poorly understood. The purpose of this study was to analyze the kinetics of bacterial dissemination and associated inflammatory responses in infected tissues in an experimental scrub typhus mouse model, following infection with the human pathogenic strain Karp. We provide a thorough analysis of O. tsutsugamushi infection in inbred Balb/c mice using footpad inoculation, which is close to the natural way of infection. By a novel, highly sensitive qPCR targeting the multi copy traD genes, we quantitatively monitored the spread of O. tsutsugamushi Karp from the skin inoculation site via the regional lymph node to the internal target organs. The highest bacterial loads were measured in the lung. Using confocal imaging, we also detected O. tsutsugamushi at the single cell level in the lung and found a predominant macrophage rather than endothelial localization. Immunohistochemical analysis of infiltrates in lung and brain revealed differently composed lesions with specific localizations: iNOS-expressing macrophages were frequent in infiltrative parenchymal noduli, but uncommon in perivascular lesions within these organs. Quantitative analysis of the macrophage response by immunohistochemistry in liver, heart, lung and brain demonstrated an early onset of macrophage activation in the liver. Serum levels of interferon (IFN)-γ were increased during the acute infection, and we showed that IFN-γ contributed to iNOS-dependent bacterial growth control. Our data show that upon inoculation to the skin, O. tsutsugamushi spreads systemically to a large number of organs and gives rise to organ-specific inflammation patterns. The findings suggest an essential role for the lung in the pathogenesis of scrub typhus. The model will allow detailed studies on host-pathogen interaction and provide further insight into the pathogenesis of O. tsutsugamushi infection.
Subject(s)
Inflammation/etiology , Orientia tsutsugamushi/isolation & purification , Scrub Typhus/immunology , Animals , Cells, Cultured , Disease Models, Animal , Humans , Interferon-gamma/physiology , Lung/pathology , Macrophage Activation , Meningoencephalitis/immunology , Mice , Mice, Inbred BALB C , Polymerase Chain Reaction , Scrub Typhus/microbiology , Scrub Typhus/pathologyABSTRACT
BACKGROUND: Empathy is an outcome-relevant physician characteristic and thus a crucial component of high-quality communication in health care. However, the factors that promote and inhibit the development of empathy during medical education have not been extensively researched. Also, currently there is no explicit research on the perspective of practicing physicians on the subject. Therefore the aim of our study was to explore physicians' views of the positive and negative influences on the development of empathy during their medical education, as well as in their everyday work as physicians. METHOD: We administered a written Qualitative Short Survey to 63 physicians in seven specialties. They were able to respond anonymously. Our open-ended question was: "What educational content in the course of your studies and/or your specialist training had a positive or negative effect on your empathy?" We analyzed the data using thematic content analysis following Mayring's approach. RESULTS: Forty-two physicians took part in our survey. All together, they mentioned 68 specific factors (37 positive, 29 negative, 2 neutral) from which six themes emerged: 1. In general, medical education does not promote the development of empathy. 2. Recognizing the psycho-social dimensions of care fosters empathy. 3. Interactions with patients in medical practice promote empathy. 4. Physicians' active self-development through reflective practice helps the development of empathy. 5. Interactions with colleagues can both promote and inhibit empathy through their role modeling of empathic and non-empathic behavior. 6. Stress, time pressure, and adverse working conditions are detrimental to empathy development. CONCLUSIONS: Our results provide an overview of what might influence the development of clinical empathy, as well as hypothetical conclusions about how to promote it. Reflective practice seems to be lacking in current medical curricula and could be incorporated. Raising physicians' awareness of the psycho-social dimension of disease, and of the impact of peer influence and role modeling, seems promising in this regard, too. Stress and well-being seem to be closely related to physician empathy, and their modulation must take into account individual, social, and organizational factors. Further research should investigate whether or how these hypothetical conclusions can deepen our understanding of the determinants of physician empathy in order to help its promotion.
Subject(s)
Education, Medical , Empathy , Physicians/psychology , Adult , Aged , Attitude of Health Personnel , Data Collection , Female , Humans , Male , Middle Aged , Qualitative ResearchABSTRACT
BACKGROUND: Mice lacking the type I interferon receptor (IFNAR-/- mice) reproduce relevant aspects of Crimean-Congo hemorrhagic fever (CCHF) in humans, including liver damage. We aimed at characterizing the liver pathology in CCHF virus-infected IFNAR-/- mice by immunohistochemistry and employed the model to evaluate the antiviral efficacy of ribavirin, arbidol, and T-705 against CCHF virus. METHODOLOGY/PRINCIPAL FINDINGS: CCHF virus-infected IFNAR-/- mice died 2-6 days post infection with elevated aminotransferase levels and high virus titers in blood and organs. Main pathological alteration was acute hepatitis with extensive bridging necrosis, reactive hepatocyte proliferation, and mild to moderate inflammatory response with monocyte/macrophage activation. Virus-infected and apoptotic hepatocytes clustered in the necrotic areas. Ribavirin, arbidol, and T-705 suppressed virus replication in vitro by ≥3 log units (IC50 0.6-2.8 µg/ml; IC90 1.2-4.7 µg/ml). Ribavirin [100 mg/(kg×d)] did not increase the survival rate of IFNAR-/- mice, but prolonged the time to death (p<0.001) and reduced the aminotransferase levels and the virus titers. Arbidol [150 mg/(kg×d)] had no efficacy in vivo. Animals treated with T-705 at 1 h [15, 30, and 300 mg/(kg×d)] or up to 2 days [300 mg/(kg×d)] post infection survived, showed no signs of disease, and had no virus in blood and organs. Co-administration of ribavirin and T-705 yielded beneficial rather than adverse effects. CONCLUSIONS/SIGNIFICANCE: Activated hepatic macrophages and monocyte-derived cells may play a role in the proinflammatory cytokine response in CCHF. Clustering of infected hepatocytes in necrotic areas without marked inflammation suggests viral cytopathic effects. T-705 is highly potent against CCHF virus in vitro and in vivo. Its in vivo efficacy exceeds that of the current standard drug for treatment of CCHF, ribavirin.
Subject(s)
Amides/pharmacology , Antiviral Agents/pharmacology , Hemorrhagic Fever Virus, Crimean-Congo/drug effects , Hemorrhagic Fever, Crimean/virology , Indoles/pharmacology , Pyrazines/pharmacology , Ribavirin/pharmacology , Amides/administration & dosage , Amides/therapeutic use , Amides/toxicity , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/therapeutic use , Antiviral Agents/toxicity , Chlorocebus aethiops , Disease Models, Animal , Female , Hemorrhagic Fever, Crimean/drug therapy , Indoles/administration & dosage , Indoles/therapeutic use , Indoles/toxicity , Liver/chemistry , Liver/immunology , Liver/pathology , Liver/virology , Male , Mice , Mice, Transgenic , Pyrazines/administration & dosage , Pyrazines/therapeutic use , Pyrazines/toxicity , Receptor, Interferon alpha-beta/genetics , Ribavirin/administration & dosage , Ribavirin/therapeutic use , Ribavirin/toxicity , Vero CellsABSTRACT
A feature of neurodegenerative diseases is the intraneuronal accumulation of misfolded proteins. In familial encephalopathy with neuroserpin inclusion bodies (FENIB), mutations in neuroserpin lead to accumulation of neuroserpin polymers within the endoplasmic reticulum (ER) of neurons. Cell culture based studies have shown that ER-associated degradation (ERAD) is involved in clearance of mutant neuroserpin. Here, we investigate how mutant neuroserpin is delivered to ERAD using cell culture and a murine model of FENIB. We show that the ER-lectin OS-9 but not XTP3-B is involved in ERAD of mutant neuroserpin. OS-9 binds mutant neuroserpin and the removal of glycosylation sites leads to increased neuroserpin protein load whereas overexpression of OS-9 decreases mutant neuroserpin. In FENIB mice, OS-9 but not XTP3-B is differently expressed and impairment of ERAD by partial inhibition of the ubiquitin proteasome system leads to increased neuroserpin protein load. These findings show that OS-9 delivers mutant neuroserpin to ERAD by recognition of glycan side chains and provide the first in vivo proof of involvement of ERAD in degradation of mutant neuroserpin.
Subject(s)
Endoplasmic Reticulum-Associated Degradation/genetics , Epilepsies, Myoclonic/genetics , Heredodegenerative Disorders, Nervous System/genetics , Lectins/metabolism , Mutation , Neoplasm Proteins/metabolism , Neuropeptides/genetics , Neuropeptides/metabolism , Serpins/genetics , Serpins/metabolism , Animals , Cells, Cultured , Disease Models, Animal , Endoplasmic Reticulum , Epilepsies, Myoclonic/metabolism , Glycosylation , Heredodegenerative Disorders, Nervous System/metabolism , Humans , Mice, Transgenic , Polysaccharides/metabolism , Proteasome Endopeptidase Complex , Protein Binding , Protein Transport , Proteolysis , Ubiquitin , NeuroserpinABSTRACT
BACKGROUND: In human and animal prion diseases, pathological prion protein, PrPSc, as well as prion infectivity is mainly found in the central nervous system, but also in lymphoid organs and muscle. Pathophysiology of prion colonization of lymphoid organs has been studied intensively, yet how myositis influences prion accumulation in muscle is unknown. RESULT: We have investigated the influence of myositis on PrPSc accumulation and prion infectivity in two distinct mouse models of experimental autoimmune myositis. Furthermore, we have addressed the relevance of PrPC expression in the lymphoreticular system in myositis by generating bone marrow chimeras.Here we show that myositis positively influences muscular PrPSc accumulation at preclinical time points and that PrPC-expression in the lymphoid system is critical for this. In muscle, PrPSc and prion infectivity are uncoupled with detectable PrPSc but no prion infectivity at preclinical time points. Muscle has an intrinsically high ability to clear PrPSc once myositis has ceased, possibly involving autophagy. CONCLUSION: Our findings provide new insights into the pathophysiology of prion colonization in muscle pointing out that myositis leads to enhanced prion colonization of muscle in subclinical prion disease.
Subject(s)
Muscles/metabolism , Nervous System Autoimmune Disease, Experimental/metabolism , PrPSc Proteins/metabolism , Animals , Blotting, Western , Disease Progression , Immunohistochemistry , Mice, Inbred C57BL , Mice, Knockout , Prion Proteins , Prions/genetics , Prions/metabolism , Radiation Chimera , Time FactorsABSTRACT
Prion amyloidosis occurred in the heart of 1 of 3 macaques intraperitoneally inoculated with bovine spongiform encephalopathy prions. This macaque had a remarkably long duration of disease and signs of cardiac distress. Variant Creutzfeldt-Jakob disease, caused by transmission of bovine spongiform encephalopathy to humans, may manifest with cardiac symptoms from prion-amyloid cardiomyopathy.
Subject(s)
Amyloidosis/pathology , Cardiomyopathies/etiology , Cardiomyopathies/pathology , Creutzfeldt-Jakob Syndrome/pathology , Creutzfeldt-Jakob Syndrome/transmission , Encephalopathy, Bovine Spongiform/transmission , Animals , Brain/pathology , Cattle , Encephalopathy, Bovine Spongiform/pathology , Macaca mulatta , Muscle, Skeletal/pathology , Myocardium/pathologyABSTRACT
The only approved pharmacological treatment for ischemic stroke is intravenous administration of plasminogen activator (tPA) to re-canalize the occluded cerebral vessel. Not only reperfusion but also tPA itself can induce an inflammatory response. Microglia are the innate immune cells of the central nervous system and the first immune cells to become activated in stroke. Neuroserpin, an endogenous inhibitor of tPA, is up-regulated following cerebral ischemia. To examine neuroserpin-dependent mechanisms of neuroprotection in stroke, we studied neuroserpin deficient (Ns(-/-))mice in an animal model of temporal focal ischemic stroke. Infarct size and neurological outcome were worse in neuroserpin deficient mice even though the fibrinolytic activity in the ischemic brain was increased. The increased infarct size was paralleled by a selective increase in proinflammatory microglia activation in Ns(-/-) mice. Our results show excessive microglial activation in Ns(-/-) mice mediated by an increased activity of tPA. This activation results in a worse outcome further underscoring the potential detrimental proinflammatory effects of tPA.
Subject(s)
Brain Ischemia/pathology , Microglia/pathology , Neuropeptides/genetics , Serpins/genetics , Stroke/pathology , Tissue Plasminogen Activator/genetics , Animals , Brain Ischemia/genetics , Brain Ischemia/immunology , Disease Models, Animal , Gene Expression Regulation , Inflammation , Mice , Mice, Knockout , Microglia/immunology , Neuropeptides/deficiency , Neutrophil Infiltration , Serpins/deficiency , Stroke/genetics , Stroke/immunology , Tissue Plasminogen Activator/immunology , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/metabolism , NeuroserpinABSTRACT
OBJECTIVE: Professional capabilities, such as empathy and patient-centeredness, decline during medical education. Reflective practice is advocated for teaching these capabilities. The Clinical Reflection Training (CRT) is a reflective practice intervention using the professional dilemmas faced by medical students during clinical practice. The aim of this study was to evaluate students' perceptions of the helpfulness of the CRT and its effects on their medical education. METHODS: Eighteen semi-structured interviews were conducted with medical students who had participated in the CRT. Content analysis was used to analyze the interview data. RESULTS: Medical students did not feel adequately prepared to manage the difficult personal and interpersonal problems frequently encountered in clinical practice. They reported that the CRT reduces stress, improves patient care and serves as a tool for professional development. CONCLUSION: The CRT may be a useful tool for developing professionalism during medical education, reducing stress and enhancing the quality of patient care. PRACTICE IMPLICATIONS: Providing students with reflective practice training that draws on their current personal clinical problems in order to improve their clinical work may be a productive investment in personal professional development, physician health, and quality improvement.
Subject(s)
Clinical Competence/standards , Education, Medical/organization & administration , Learning , Patient Care/standards , Students, Medical/psychology , Adult , Attitude of Health Personnel , Humans , Interviews as Topic , Qualitative Research , Quality ImprovementABSTRACT
Objectives. To examine the impact of active student participation on quality of care in an integrative inpatient setting. Methods. Over a two-year period, we surveyed all patients treated on the Clinical Education Ward for Integrative Medicine (CEWIM), where final-year medical students are integrated into an internal medicine ward complementing conventional medicine with anthroposophic medicine. Patients treated on the regular wards of the same internal medicine department served as the control group (CG). General quality of care was studied with the Picker Inpatient Questionnaire, physician empathy with the Consultation and Relational Empathy measure, and patient enablement with the Patient Enablement Index. ANCOVA was used to control for covariates while examining significant differences between both patient groups. Results. Comparison of the CG wards and the CEWIM revealed no significant differences in medical treatment success. The CEWIM, however, achieved better results for physician-patient interaction, physician empathy, and patient enablement. Eighty Percent of the CEWIM patients rated student participation as positively impacting quality of care. Conclusion. Our results indicate that incorporating students in an integrative healthcare setting may result in greater patient centeredness. Further studies are needed to determine whether this is due to organizational advantages, students' empathic activity, the impact of teaching, or learner-teacher interaction.
ABSTRACT
Prion diseases are fatal neurodegenerative disorders. An important step in disease pathophysiology is the conversion of cellular prion protein (PrP(C)) to disease-associated misfolded conformers (PrP(Sc)). These misfolded PrP variants are a common component of prion infectivity and are detectable in diseased brain and lymphoreticular organs such as spleen. In the latter, PrP(Sc) is thought to replicate mainly in follicular dendritic cells within spleen follicles. Although the presence of PrP(Sc) is a hallmark for prion disease and serves as a main diagnostic criterion, in certain instances the amount of PrP(Sc) does not correlate well with neurotoxicity or prion infectivity. Therefore, it has been proposed that prions might be a mixture of different conformers and aggregates with differing properties. This study investigated the impact of disruption of spleen architecture by neoplasia on the abundance of different PrP species in spleens of prion-infected mice. Although follicular integrity was completely disturbed, titres of prion infectivity in neoplastic spleens were not significantly altered, yet no protease-resistant PrP(Sc) was detectable. Instead, unique protease-sensitive prion species could be detected in neoplastic spleens. These results indicate the dissociation of PrP(Sc) and prion infectivity and showed the presence of non-PrP(Sc) PrP species in spleen with divergent biochemical properties that become apparent after tissue architecture disruption.