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BACKGROUND: In 1945 the artist and art collector J. Dubuffet coined the term Art brut for original works by psychiatric inmates that had been created outside of traditions and art movements. In the following decades these works were at the center of negotiation processes in which not only psychiatrists but also exhibition organizers, gallery owners etc. increasingly became involved. OBJECTIVE: Based on the evaluation of four exemplary pairs of psychiatrists and artist patients (H. Müller-Suur-P. Goesch; M. in der Beeck-E. Spießbach; J. Porret-Forel-A. Corbaz; L. Navratil-R. Limberger), this study explores the field of tension between art and psychiatry after 1945. MATERIAL AND METHODS: The results of the subproject "Normal#Crazy Art. Works from a Psychiatric Context between Diagnostics and Aesthetics after 1945" of the German Research Foundation (DFG) research group "Normal#Crazy" (FOR 3031) are based on the evaluation of archival material, estates, interviews with contemporary witnesses and contemporary media. RESULTS: It is shown that different attitudes of the psychiatrists towards "their" artist patients strongly influenced their entry into the art world. In this context, impulses from beyond psychiatry were important in order to expand purely diagnostic views of the works with other approaches. DISCUSSION: The renewed interest in the individual creativity of patients after 1945 can be understood as a reaction to their dehumanization under fascism and National Socialism; however, the focus on the pathologized personality of artist patients could obscure alternative perspectives on their art, just as the disposal of their works by psychiatrists could hinder their dissemination.
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Arte , Transtornos Mentais , Médicos , Psiquiatria , Humanos , Transtornos Mentais/psicologia , CriatividadeRESUMO
PURPOSE: Preimplantation genetic testing (PGT) using Karyomapping is used to screen embryos for single gene disorders prior to implantation. While Karyomapping is not designed to screen for abnormalities in chromosome copy number, this testing is based upon a genome-wide analysis of single nucleotide polymorphisms (SNP) and, as such, some chromosome abnormalities are detected. The aim of this study was to validate whether Karyomapping could provide reliable and accurate PGT for a paternal 46,XY,t(10;19)(p15;p13.3) reciprocal translocation. METHODS: Feasibility/validation for PGT was performed using DNA from the couple, as well as DNA from the paternal parents and from a previous unbalanced pregnancy. Karyomapping was performed using Illumina's HumanKaryomap-12 BeadChip microarray technology. SNP analysis was performed using BlueFuse Multi software (Illumina). Transmission of the translocation was assessed through the analysis of SNP markers on the chromosome regions of interest. RESULTS: PGT-SR was determined to be feasible as chromosomal SNP analysis could reliably distinguish normal/balanced outcomes from all unbalanced outcomes. The couple transferred a normal/balanced embryo in an elective single embryo transfer procedure following 2 IVF/PGT-SR cycles. A clinical pregnancy was achieved. CONCLUSION: This is the first report of PGT-SR test validation using Karyomapping for a 46,XY,t(10;19)(p15;p13.3) reciprocal translocation. Karyomapping may offer a means of detecting unbalanced forms of chromosome rearrangements when other PGT platforms fail.
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Mapeamento Cromossômico/métodos , Doenças Genéticas Inatas/prevenção & controle , Testes Genéticos/métodos , Cariotipagem/métodos , Herança Paterna/genética , Diagnóstico Pré-Implantação/métodos , Translocação Genética , Adulto , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/embriologia , Doenças Genéticas Inatas/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , GravidezRESUMO
BACKGROUND: Sex differences in the calculation of coronary heart disease risk have been analysed extensively. However, data on coronary plaque morphology diverge. We analysed plaque characteristics in patients with suspected coronary artery disease (CAD) and defined prognostic factors using coronary computed tomography angiography (CCTA). METHODS: A total of 6,050 consecutive patients underwent CCTA and were enrolled in the registry. Patients with known CAD were excluded. The patients were propensity score matched (1:1 male:female) for age and known coronary risk factors. Coronary arteries were evaluated for stenosis, plaque types (non-calcified, mixed and calcified) and high-risk plaque features (napkin-ring sign, low-attenuation plaque, spotty calcifications, positive remodelling). Clinical follow-up was performed. RESULTS: A total of 1,050 patients (525 female, 525 male) in matched cohorts were selected for analysis. CCTA showed significantly higher calcium scores for males (mean 180.5 vs 67.8 AU, pâ¯< 0.0001) and a higher rate of CAD (66.0% vs 34.1%, pâ¯< 0.0001). In a total of 16,800 segments, males had significantly more plaques (861 vs 752, pâ¯< 0.0001) with a significantly larger proportion of calcified plaques, while females had more mixed and non-calcified plaques (33.5% vs 24.4%, pâ¯= 0.006 and 24.1% vs 13.6%, pâ¯= 0.22, respectively). After a mean follow-up of 5.6 years, major adverse cardiac event (MACE) rate was 5.3% in male and 1.9% in female patients (pâ¯< 0.05). The relative odds ratio for high-risk plaque features to predict MACE was higher in females. CONCLUSION: Based on a higher relative risk for women with high-risk plaque features, the findings of our study support the increased importance of a differentiated qualitative plaque analysis to improve the risk stratification for both sexes.
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AIMS: Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motoneurons and progressive muscle wasting. Inflammatory processes, mediated by non-neuronal cells, such as glial cells, are known to contribute to disease progression. Inflammasomes consist of pattern recognition receptors (PRRs), apoptosis-associated speck-like protein (ASC) and caspase 1 and are essential for interleukin (IL) processing and a rapid immune response after tissue damage. Recently, we described inflammasome activation in the spinal cord of ALS patients and in SOD1(G93A) ALS mice. Since pathological changes in the skeletal muscle are early events in ALS, we hypothesized that PRRs might be abnormally expressed in muscle fibre degeneration. METHODS: Western blot analysis, real-time PCR and immunohistochemistry were performed with muscle tissue from presymptomatic and early-symptomatic male SOD1(G93A) mice and with muscle biopsies of control and sporadic ALS (sALS) patients. Analysed PRRs include nucleotide-binding oligomerization domain-like (NOD-like) receptor protein 1 (NLRP1), NLR protein 3 (NLRP3), NLR family CARD domain-containing 4 (NLRC4) and absent in melanoma 2. Additionally, expression levels of ASC, caspase 1, interleukin 1 beta (IL1ß) and interleukin 18 (IL18) were evaluated. RESULTS: Expression of PRRs and ASC was detected in murine and human tissue. The PRR NLRC4, caspase 1 and IL1ß were significantly elevated in denervated muscle of SOD1(G93A) mice and sALS patients. Furthermore, levels of caspase 1 and IL1ß were already increased in presymptomatic animals. CONCLUSION: Our findings suggest that increased inflammasome activation may be involved in skeletal muscle pathology in ALS. Furthermore, elevated levels of NLRC4, caspase 1 and IL1ß reflect early changes in the skeletal muscle and may contribute to the denervation process.
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Esclerose Lateral Amiotrófica/metabolismo , Inflamassomos/metabolismo , Músculo Esquelético/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Humanos , Camundongos , Músculo Esquelético/patologia , Superóxido Dismutase-1/metabolismoRESUMO
STUDY QUESTION: Is next generation sequencing (NGS) capable of detecting smaller sub-chromosomal rearrangements in human embryos than the manufacturer's quoted resolution suggests? SUMMARY ANSWER: NGS was able to detect unbalanced chromosome segments smaller than the manufacturer's resolution. WHAT IS KNOWN ALREADY: Array Comparative Genomic Hybridization (array-CGH) has been the gold standard platform used for PGD of chromosome rearrangements. NGS is a viable alternative to array-CGH for PGD of chromosome arrangements given that the manufacturer's guidelines quote a resolution of ≥20 Mb. However, as many patients carry a chromosome rearrangement <20 Mb, the detection limits of NGS warrant further investigation. STUDY DESIGN, SIZE, DURATION: This study involved a retrospective assessment of stored DNA samples from embryos that had previously been diagnosed as unbalanced by array-CGH as part of routine PGD in two separate IVF clinics between November 2013 and April 2017. SurePlex whole genome amplification (WGA) products derived from DNA extracted from an embryo biopsy sample known to carry an unbalanced form of a chromosome rearrangement were subjected to a specific NGS workflow (VeriSeq PGS). The results from the two technologies were compared for each sample. PARTICIPANTS/MATERIALS, SETTING, METHODS: WGA products from 200 embryos known to carry unbalanced rearrangements were sequenced and analysed. These embryos had been created by 75 patients known to carry a chromosome rearrangement (68 reciprocal translocations, 3 pericentric inversions, 1 paracentric inversion, 2 insertions and 1 dual reciprocal and inversion). Each sample was assessed for the size of the segmental gain/loss (Mb), copy number for each segment and chromosome, segregation pattern, the number of bins in the analysis software used and concordance with array-CGH results. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 294 unbalanced chromosome segments were assessed. NGS was capable of detecting 285/294 (97%) unbalanced segments previously identified using array-CGH. The final PGD diagnosis was concordant for 200/200 (100%) embryos. In total, 44/75 (59%) patients contained an unbalanced chromosome segment below the quoted 20 Mb manufacturer's stated resolution. Of these, 35/44 (80%) patients had segments that were able to be detected using NGS, whilst maintaining clinical outcome concordance. LIMITATIONS, REASONS FOR CAUTION: Our study subset did not include any rearrangements involving the Y chromosome. NGS has less available bins per chromosome compared to the array-CGH platform used, thus it remains possible that chromosome rearrangements predicted to be small but still detectable by array-CGH may not be feasible for testing using NGS. This should be considered when undertaking a theoretical feasibility assessment for detecting the chromosome rearrangement in question. Only one specific workflow for WGA and NGS was investigated in this study. WIDER IMPLICATIONS OF THE FINDINGS: This study has shown that NGS is available for the detection of unbalanced chromosome rearrangements ≥10 Mb. STUDY FUNDING/COMPETING INTEREST(S): Part sponsorship of the VeriSeq PGS kits used was provided by Illumina. The remainder of the kits were provided by two commercial IVF clinics. None of the authors has any conflicting interests to declare. TRIAL REGISTRATION NUMBER: N/A.
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Aberrações Cromossômicas , Hibridização Genômica Comparativa , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Diagnóstico Pré-Implantação/métodos , Técnicas de Reprodução Assistida/efeitos adversos , Hibridização Genômica Comparativa/normas , Feminino , Testes Genéticos/normas , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Limite de Detecção , Valor Preditivo dos Testes , Gravidez , Diagnóstico Pré-Implantação/normas , Reprodutibilidade dos Testes , Estudos Retrospectivos , Austrália do Sul , VitóriaRESUMO
BACKGROUND: Chronic inflammatory diseases are complex disorders, which due to their multitude of manifestations require interdisciplinary treatment. OBJECTIVE: The aim of this article is to provide a brief overview of current strategies and innovations for chronic inflammatory bowel diseases. METHODS: A literature search was carried out in PubMed. RESULTS: Shared pathophysiological pathways in chronic inflammatory diseases sometimes lead to common targets in treatment; however, there are also relevant specific differences with respect to treatment. CONCLUSION: Due to the many extraintestinal organ manifestations, chronic inflammatory bowel diseases require interdisciplinary treatment.
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Gastroenterologistas , Doenças Inflamatórias Intestinais , Dermatopatias , Humanos , ReumatologistasRESUMO
Oxidative stress critically contributes to the pathogenesis of a variety of neurodegenerative diseases such as multiple sclerosis. Astrocytes are the main regulators of oxidative homeostasis in the brain and dysregulation of these cells likely contributes to the accumulation of oxidative damage. The nuclear factor erythroid 2-related factor 2 (Nrf2) is the main transcriptional regulator of the anti-oxidant stress defense. In this study, we elucidate the effects of astrocytic Nrf2-activation on brain-intrinsic inflammation and lesion development. Cells deficient for the Nrf2 repressor kelch-like ECH-associated protein 1 (Keap1) are characterized by hyperactivation of Nrf2-signaling. Therefore, wild type mice and mice with a GFAP-specific Keap1-deletion were fed with 0.25% cuprizone for 1 or 3 weeks. Cuprizone intoxication induced pronounced oligodendrocyte loss, demyelination and reactive gliosis in wild type animals. In contrast, astrocyte-specific Nrf2-activation was sufficient to prevent oligodendrocyte loss and demyelination, to ameliorate brain intrinsic inflammation and to counteract axonal damage. Our results highlight the potential of the Nrf2/ARE system for the treatment of neuroinflammation in general and of multiple sclerosis in particular. © GLIA 2016;64:2219-2230.
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Astrócitos/metabolismo , Doenças Desmielinizantes/etiologia , Regulação da Expressão Gênica/fisiologia , Esclerose Múltipla/complicações , Esclerose Múltipla/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Cuprizona/toxicidade , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibidores da Monoaminoxidase/toxicidade , Esclerose Múltipla/induzido quimicamente , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Tiorredoxina Redutase 1/genética , Tiorredoxina Redutase 1/metabolismoRESUMO
We report on a case of catheter-related thrombosis after 7day catheter placement during intravascular temperature management (IVTM), in spite of the use of prophylactic anticoagulants. There were no clinical sequelae. According to the literature, occult thrombosis during ITVM could be more frequent than previously reported and dedicated monitoring for potential thrombosis may be indicated. However, a study comparing IVTM with surface cooling found no differences in clinical outcome. Therefore, n either of the methods can be recommended over the other. Further studies should evaluate the rate of occult thrombosis during the use of both cooling methods.
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Temperatura Corporal , Cateteres Venosos Centrais/efeitos adversos , Trombose/etiologia , Adulto , Vasos Sanguíneos , Contusão Encefálica/fisiopatologia , Contusão Encefálica/cirurgia , Cateterismo Venoso Central , Humanos , Masculino , Procedimentos NeurocirúrgicosRESUMO
Intracellular accumulations of mutant, misfolded proteins are major pathological hallmarks of amyotrophic lateral sclerosis (ALS) and related disorders. Recently, mutations in Sigma receptor 1 (SigR1) have been found to cause a form of ALS and frontotemporal lobar degeneration (FTLD). Our goal was to pinpoint alterations and modifications of SigR1 in ALS and to determine how these changes contribute to the pathogenesis of ALS. In the present study, we found that levels of the SigR1 protein were reduced in lumbar ALS patient spinal cord. SigR1 was abnormally accumulated in enlarged C-terminals and endoplasmic reticulum (ER) structures of alpha motor neurons. These accumulations co-localized with the 20s proteasome subunit. SigR1 accumulations were also observed in SOD1 transgenic mice, cultured ALS-8 patient's fibroblasts with the P56S-VAPB mutation and in neuronal cell culture models. Along with the accumulation of SigR1 and several other proteins involved in protein quality control, severe disturbances in the unfolded protein response and impairment of protein degradation pathways were detected in the above-mentioned cell culture systems. Furthermore, shRNA knockdown of SigR1 lead to deranged calcium signaling and caused abnormalities in ER and Golgi structures in cultured NSC-34 cells. Finally, pharmacological activation of SigR1 induced the clearance of mutant protein aggregates in these cells. Our results support the notion that SigR1 is abnormally modified and contributes to the pathogenesis of ALS.
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Esclerose Lateral Amiotrófica/genética , Degeneração Lobar Frontotemporal/genética , Proteínas Mutantes , Neurônios/metabolismo , Receptores sigma/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Sinalização do Cálcio , Modelos Animais de Doenças , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Degeneração Lobar Frontotemporal/patologia , Vértebras Lombares/metabolismo , Vértebras Lombares/patologia , Camundongos , Camundongos Transgênicos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Neurônios/citologia , Neurônios/patologia , Dobramento de Proteína , Proteólise , Receptores sigma/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologia , Superóxido Dismutase/genética , Resposta a Proteínas não Dobradas , Receptor Sigma-1RESUMO
OBJECTIVE: Fc-gamma receptors (FcγRs) have been shown to play a crucial role in cartilage degradation during experimental arthritis. Although most of their effect on cartilage degradation has been attributed to their potential to promote inflammation in the presence of immunoglobulins, activating FcγRs promote cartilage degeneration in antigen-induced arthritis (AIA) independently of the level of inflammation. This prompted us to investigate, whether FcγRs may also play a role in osteoarthritis (OA)-related cartilage degradation. METHODS: FcγR expression was measured by RT-PCR and FACS in murine cartilage tissue and chondrocytes. Experimental OA was induced by destabilisation of the medial meniscus (DMM) in WT mice and animals lacking either activating (Fc receptor γ-chain-deficient) or inhibitory (FcγRIIB-deficient) FcγRs. Cartilage damage was investigated histologically 8 weeks post-surgery by assessing proteoglycan loss and structural damage according to OARSI recommendations. Osteophyte size was measured to investigate alterations in bone turnover. RESULTS: Expression analyses revealed significant levels for all four types of murine FcγRs in mouse chondrocytes and cartilage tissue from newborn and 8-week-old mice. Surprisingly, yet, ablation of either activating or inhibitory FcγRs did not affect cartilage damage or bone turnover during DMM-induced OA in mice. CONCLUSION: While FcγRs appear to have a crucial role in cartilage degradation during inflammatory arthritis our data indicate that FcγRs do not influence cartilage destruction in experimental OA. This indicates that a certain threshold of inflammation is a prerequisite for FcγR-induced cartilage destruction in arthritis.
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Artrite Experimental/imunologia , Cartilagem Articular/imunologia , Osteoartrite/imunologia , Receptores de IgG/imunologia , Animais , Artrite Experimental/patologia , Cartilagem Articular/patologia , Células Cultivadas , Condrócitos/imunologia , Expressão Gênica , Camundongos Endogâmicos C57BL , Osteófito/patologia , Receptores de IgG/biossíntese , Receptores de IgG/deficiência , Receptores de IgG/genéticaRESUMO
The role of classical estrogen receptors (ERs) in priming female reproductive behavior has been studied previously; however, the participation of this receptor during activation of estrous behavior has not been extensively studied. The purpose of this work was to test the possibility that the facilitation of lordosis behavior in estrogen-primed rats by progesterone (P) and its 5α- and 5ß-reduced metabolites, gonadotropin-releasing hormone (GnRH), leptin, prostaglandin E2 (PGE2) and vagino-cervical stimulation (VCS) involves interactions with classical ERs by using the selective ER modulator, tamoxifen. To further assess the role of ERs, we also explored the effects of the pure ER antagonist, ICI182780 (ICI), on estrous behavior induced by P and GnRH. Ovariectomized, estrogen-primed rats (5µg estradiol benzoate 40h earlier) were injected intraventricularly with the above-mentioned compounds, or they received VCS. All compounds and VCS effectively facilitated estrous behavior when tested at 60, 120 or 240min after infusion or application of VCS. Intraventricular infusion of tamoxifen (5µg), 30min before, significantly attenuated estrous behaviors induced in estradiol-primed rats by P, most of its 5α- and 5ß-reduced metabolites, GnRH, and PGE2, but not by VCS. Although there was a trend for reduction, tamoxifen did not significantly decrease lordosis in females treated with 5ß-pregnan-3,20-dione. ICI also inhibited lordosis behavior induced by P and GnRH at some testing intervals. These results suggest that activation of classical ERs participates in the triggering effects on estrous behavior induced by agents with different chemical structures that do not bind directly to ERs.
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Comportamento Animal/efeitos dos fármacos , Dinoprostona/farmacologia , Ciclo Estral/efeitos dos fármacos , Peptídeos/farmacologia , Progestinas/farmacologia , Receptores de Estrogênio/fisiologia , Animais , Antagonistas de Estrogênios/farmacologia , Feminino , Hormônio Liberador de Gonadotropina/farmacologia , Injeções Intraventriculares , Leptina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Estrogênio/efeitos dos fármacos , Tamoxifeno/farmacologiaRESUMO
The influence of transverse mixing on competitive aerobic and anaerobic biodegradation of a hydrocarbon plume was investigated using a two-dimensional, bench-scale flow-through laboratory tank experiment. In the first part of the experiment aerobic degradation of increasing toluene concentrations was carried out by the aerobic strain Pseudomonas putida F1. Successively, ethylbenzene (injected as a mixture of unlabeled and fully deuterium-labeled isotopologues) substituted toluene; nitrate was added as additional electron acceptor and the anaerobic denitrifying strain Aromatoleum aromaticum EbN1 was inoculated to study competitive degradation under aerobic /anaerobic conditions. The spatial distribution of anaerobic degradation was resolved by measurements of compound-specific stable isotope fractionation induced by the anaerobic strain as well as compound concentrations. A fully transient numerical reactive transport model was employed and calibrated using measurements of electron donors, acceptors and isotope fractionation. The aerobic phases of the experiment were successfully reproduced using a double Monod kinetic growth model and assuming an initial homogeneous distribution of P. putida F1. Investigation of the competitive degradation phase shows that the observed isotopic pattern cannot be explained by transverse mixing driven biodegradation only, but also depends on the inoculation process of the anaerobic strain. Transient concentrations of electron acceptors and donors are well reproduced by the model, showing its ability to simulate transient competitive biodegradation.
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Derivados de Benzeno/metabolismo , Modelos Estatísticos , Pseudomonas putida/metabolismo , Rhodocyclaceae/metabolismo , Tolueno/metabolismo , Poluentes Químicos da Água/metabolismo , Aerobiose , Anaerobiose , Biodegradação Ambiental , Transporte de Elétrons , Água Doce/química , CinéticaRESUMO
The p7 protein of hepatitis C virus (HCV) is a small, integral membrane protein that plays a critical role in virus replication. Recently, we reported two intergenotypic JFH1 chimeric viruses encoding the partial or full-length p7 protein of the HCV-A strain of genotype 1b (GT1b; Virology; 2007; 360:134). In this study, we determined the consensus sequences of the entire polyprotein coding regions of the wild-type JFH1 and the revertant chimeric viruses and identified predominant amino acid substitutions in core (K74M), NS2 (T23N, H99P) and NS5A (D251G). Forward genetic analysis demonstrated that all single mutations restored the infectivity of the defective chimeric genomes suggesting that the infectious virus production involves the association of p7 with specific regions in core, NS2 and NS5A. In addition, it was demonstrated that the NS2 T23N facilitated the generation of infectious intergenotypic chimeric virus encoding p7 from GT6 of HCV.
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Hepacivirus/fisiologia , Domínios e Motivos de Interação entre Proteínas , Proteínas do Core Viral/metabolismo , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/metabolismo , Replicação Viral , Análise Mutacional de DNA , Hepacivirus/genética , Mapeamento de Interação de Proteínas , Proteínas do Core Viral/genética , Proteínas não Estruturais Virais/genética , Proteínas Virais/genéticaRESUMO
BACKGROUND AND PURPOSE: Computed tomographic-angiography (CT-A) is becoming more accepted in detecting intracranial circulatory arrest in brain death (BD). An international consensus about the use and the parameters of this technique is currently not established. We examined intracranial contrast enhancement in CT-A after clinically confirmed BD, compared the results with electroencephalography (EEG) and Transcranial Doppler Ultrasonography (TCD) findings and developed a commonly applicable CT-A protocol. METHODS: Prospective, monocentric study between April 2008 and October 2011. EEG, TCD and CT-A were performed in 63 patients aged between 18 and 88 years (mean, 55 years) who fulfilled clinical criteria of BD. Evaluation of opacification of cerebral vascular territories in CT-A was performed in arterial as well as in venous scanning series by a neuroradiologist and a neurointensivist/neurosurgeon together. RESULTS: CT-A demonstrated a 95% sensitivity in detecting intracranial circulatory arrest when analysing arterial scanning series. We never observed venous blood return in internal cerebral veins. In three cases, BD confirmation by EEG failed because of artefacts. Confirmation of BD by TCD failed in two cases because of absent temporal window. In three cases, TCD demonstrated residual blood flow. CONCLUSION: CT-A is easily accessible in almost every hospital, offers a high spatio-temporal resolution, is operator independent and inexpensive. The results of CT-A are comparable to other established brain perfusion techniques in BD. An international consensus should be established to ascertain consistent parameters similar to fixed guidelines for other ancillary procedures to determine BD in order to prevent different scanning and evaluation protocols for detecting intracranial circulatory arrest.
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Morte Encefálica/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasos Sanguíneos/diagnóstico por imagem , Vasos Sanguíneos/patologia , Eletroencefalografia , Feminino , Humanos , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomógrafos Computadorizados , Ultrassonografia Doppler Transcraniana , Adulto JovemRESUMO
Gottfried Ewald (1888-1963) had been director of the State Hospital and Nursing Home and the University Clinic for Psychiatry from 1934. In August 1940, he refused his cooperation as a medical expert in the National Socialist's "euthanasia" operation during a discussion of the "Reich Cooperative for State Hospitals and Nursing Homes" (Reichsarbeitsgemeinschaft Heil- und Pflegeanstalten) in Berlin. Shortly afterwards Ewald wrote a comprehensive position paper against the operation which was sent to Werner Heyde, head of the "T4" medical office, and Leonardo Conti, "Reich physician leader" (Reichsärzteführer), among others.While Ewald's protest remained unsuccessful, it did neither result in any disciplinary consequences. By his own account, he decided to remain in his position on order to be able to rescue at least some of the patients of the State Hospital and Nursing Home destined for transport to the "T4" killing centres. In cooperation with colleagues at the hospital and the Provincial Association in Hanover, he partly succeeded to meet this aim through deferrals, leaves of absence, re-assessments and releases. These strategies were, however, not used to prevent the deportation of Jewish and compulsory detention patients. Thus, Ewald's protest was a partial, pragmatic circumvention of the National Socialist's "euthanasia" operation.
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Distúrbios Civis/história , Eugenia (Ciência)/história , Eutanásia/história , Hospitais Psiquiátricos/história , Socialismo Nacional/história , Psiquiatria/história , Alemanha , História do Século XXRESUMO
PURPOSE: Preimplantation Genetic Diagnosis (PGD) has proven to be a useful reproductive option for carriers of some chromosome rearrangements. The data presented in this study compares the impact of one versus two blastomere biopsy on the likelihood of achieving a PGD result, as well as the effect on subsequent embryo development and clinical outcomes. METHODS: IVF-PGD couples had either one or two blastomeres biopsied from all embryos with ≥7 blastomeres on day 3 post oocyte collection. These blastomeres were assessed for the specific chromosome rearrangement using Fluorescent In-situ Hybridisation (FISH). Further embryo development was monitored on days 4 and 5. Clinical outcomes were assessed retrospectively. RESULTS: The data shows that statistically more embryos achieved a PGD result following two blastomere biopsy, compared with one blastomere biopsy (92 % versus 88 %, respectively). Furthermore it was found that embryo development and clinical outcomes were similar between the two biopsy groups. CONCLUSIONS: Based on this analysis it appears that the biopsy of two blastomeres from embryos with ≥7 blastomeres on day 3 is a valid and successful approach for couples presenting for IVF-PGD for a chromosome rearrangement.
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Biópsia/métodos , Blastômeros/citologia , Aberrações Cromossômicas , Diagnóstico Pré-Implantação/métodos , Adulto , Transferência Embrionária/métodos , Desenvolvimento Embrionário , Feminino , Fertilização in vitro/métodos , Humanos , Hibridização in Situ Fluorescente , Gravidez , Taxa de Gravidez , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
Several lines of evidence indicate that remyelination represents one of the most effective mechanisms to achieve axonal protection. For reasons that are not yet understood, this process is often incomplete or fails in multiple sclerosis (MS). Activated astrocytes appear to be able to boost or inhibit endogenous repair processes. A better understanding of remyelination in MS and possible reasons for its failure is needed. Using the well-established toxic demyelination cuprizone model, we created lesions with either robust or impaired endogenous remyelination capacity. Lesions were analyzed for mRNA expression levels by Affymetrix GeneChip® arrays. One finding was the predominance of immune and stress response factors in the group of genes which were classified as remyelination-supporting factors. We further demonstrate that lesions with impaired remyelination capacity show weak expression of the radial-glia cell marker brain lipid binding protein (BLBP, also called B-FABP or FABP7). The expression of BLBP in activated astrocytes correlates with the presence of oligodendrocyte progenitor cells. BLBP-expressing astrocytes are also detected in experimental autoimmune encephalomyelitis during the remission phase. Furthermore, highest numbers of BLBP-expressing astrocytes were evident in lesions of early MS, whereas significantly less are present at the rim of (chronic)-active lesions from patients with long disease duration. Transfection experiments show that BLBP regulates growth factor expression in U87 astrocytoma cells. In conclusion, we provide evidence that expression of BLBP in activated astrocytes negatively correlates with disease duration and in parallel with remyelination failure.
Assuntos
Astrócitos/metabolismo , Proteínas de Transporte/biossíntese , Doenças Desmielinizantes/metabolismo , Proteínas de Ligação a Ácido Graxo/biossíntese , Esclerose Múltipla/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Adulto , Idoso , Animais , Western Blotting , Contagem de Células , Linhagem Celular Tumoral , Cuprizona , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Encefalomielite Autoimune Experimental/metabolismo , Proteína 7 de Ligação a Ácidos Graxos , Feminino , Fator 2 de Crescimento de Fibroblastos/biossíntese , Fator 2 de Crescimento de Fibroblastos/genética , Técnica Indireta de Fluorescência para Anticorpo , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Osteopontina/biossíntese , Fator de Crescimento Derivado de Plaquetas/biossíntese , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , TransfecçãoRESUMO
OBJECTIVE AND DESIGN: It has been demonstrated that changes in the normal-appearing white matter (NAWM) in multiple sclerosis precede the appearance of classical lesions. The understanding of NAWM biology in an established disease model might help to clarify why some of them progress to active demyelinating lesions. MATERIAL OR SUBJECTS: C57BL6 male mice (19-21 g) were used in this study. TREATMENT: Demyelination was induced by feeding mice a diet containing 0.2% cuprizone for up to 5 weeks. METHODS: Routine stainings (luxol fast blue, and hematoxylin and eosin) and immunohistochemistry were performed to assess myelin status and the inflammatory infiltrate. RESULTS: We demonstrated that, in the toxic demyelination cuprizone model, the corpus callosum is severely demyelinated after a 5-week cuprizone challenge (acute demyelination) whereas the fimbria of the hippocampus appear normal in routine myelin stainings. Microgliosis but not astrogliosis is evident after acute demyelination in the fimbria. Interestingly, both regions, the fimbria and the corpus callosum, demonstrated early oligodendrocyte apoptosis as well as intense microglia accumulation and activation. However, only the corpus callosum progresses to actively demyelination lesions whereas the fimbria does not. CONCLUSIONS: The applied model appears suitable for elucidating pathways which promote progression of affected tissue to an active lesion.
Assuntos
Cuprizona/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/patologia , Fármacos Neuroprotetores/farmacologia , Animais , Quelantes/farmacologia , Quelantes/uso terapêutico , Corpo Caloso/citologia , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Cuprizona/uso terapêutico , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Hipocampo/anatomia & histologia , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Fibras Nervosas Mielinizadas/patologia , Fármacos Neuroprotetores/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: The detrimental effects of metoprolol on early-phase preconditioning (pc) have been proven. The late phase of pc is mediated via gene transcription and cyclooxygenase-2 (COX-2) was identified as one of the key mediators. The effect of metoprolol on this is yet unknown as is its effect on cellular energy metabolism and reactive oxygen species (ROS) creation. METHODS: Cardiomyocytes from neonatal rats were cultured and randomly assigned to four pairs of treatment groups. In each pair, one group received metoprolol at a dose of 0.5 µg/ml medium. One pair served as a control; the others were subjected to 5 h of hypoxia 24 h after either hypoxia-induced, isoflurane-induced or no pc. Cell survival was measured with a redox indicator for cell metabolism. COX-2 transcription, ATP and ROS creation were measured. RESULTS: Whereas both ischemic and isoflurane pc produced mild beneficial effects (48.8±6.0% and 48.2±7.8% of surviving cells, respectively) compared with unpreconditioned controls (35.9±7.9%, P<0.01 for both), adding metoprolol was detrimental for both kinds of pc (hypoxia: 31.5±3.5%; isoflurane: 25.7±3.8%, P<0.001) but not in the unpreconditioned group (39.4±4.9%). mRNA for COX-2 was up to 10-fold elevated in pc cells. This induction was suppressed by metoprolol. Hypoxic and isoflurane-induced pc showed significant differences in ATP balance and ROS generation. CONCLUSION: Metoprolol abolishes the protection of both isoflurane- and hypoxia-induced late-phase pc in our model. This effect is accompanied by the blockade of COX-2 induction. The differences between hypoxic and isoflurane pc in ATP and ROS creation allow to presume distinct pathways on the mitochondrial level.