RESUMO
The concept of recovery in the care of mentally ill individuals is now firmly established both nationally and internationally. While clinical recovery focuses on a measurable ultimate goal based on the expression of symptoms with the intention of returning individuals to a premorbid state, personal recovery implies a process of personal development. The three key pillars are salutogenesis, resilience and empowerment. Collaborating with peer support workers is essential for the authentic expansion of therapy offers in line with the principles of recovery. These individuals have their own experiences with psychiatric care, which they utilize to support individuals in their unique recovery journey. The implementation process of recovery-oriented services presents a range of challenges and requires openness and a reorientation on the part of professional treatment teams.
Assuntos
Transtornos Mentais , Psiquiatria , Humanos , Transtornos Mentais/terapia , Aconselhamento , Psicoterapia , IntençãoRESUMO
BACKGROUND: Although Dementia with Lewy bodies (DLB) is the second most common form of dementia in elderly patients, it remains underdiagnosed compared with Alzheimer's (AD) and Parkinson's diseases (PD). This may be explained by overlapping clinical symptoms, e.g. Parkinsonism. While current MRI research focuses primarily on atrophy patterns of the frontal and temporal lobes, we focus on brainstem characteristics of DLB. In particular, we focused on brainstem atrophy patterns distinguishing DLB from Progressive Supranuclear Palsy (PSP) and PD based as the most common differential diagnoses. METHODS: We identified patients diagnosed with DLB, PD, PSP, and a control group (CTRL) in our psychiatric and neurological archives. All patients with competing diagnoses and without a high-quality T1 MPRAGE 3D dataset were excluded. We assessed atrophy patterns in all patients (1) manually and (2) using FastSurfer's segmentation algorithm in combination with FreeSurfer's brainstem volumetric calculations. We compared classical measurement methods and ratios with automated volumetric approaches. RESULTS: One hundred two patients were enrolled and evaluated in this study. Patients with DLB (n = 37) showed on average less atrophy of the brainstem than patients with PSP (n = 21), but a significantly more pronounced atrophy than patients with PD (n = 36) and the control group (CTRL, n = 8). The mean measured sagittal diameters of the midbrain were 8.17 ± 1.06 mm (mean ± standard deviation) for PSP, 9.45 ± 0.95 mm for DLB, 10.37 ± 0.99 mm for PD and 10.74 ± 0.70 for CTRL. The mean measured areas of the midbrain were 81 ± 18 mm2 for PSP, 105 ± 17 mm2 for DLB, 130 ± 26 mm2 for PD and 135 ± 23 mm2 for CTRL. The mean segmented volumes of the midbrain were 5595 ± 680 mm3 for PSP, 6051 ± 566 mm3 for DLB, 6646 ± 802 mm3 for PD and 6882 ± 844 mm3 for CTRL. The calculated midbrain pons ratios did not show superiority over the absolute measurements of the midbrain for distinguishing PSP from DLB. Because of the relatively uniform atrophy throughout the brainstem, the ratios were not suitable for distinguishing DLB from PD. CONCLUSIONS: DLB patients exhibit homogenous atrophy of the brainstem and can be distinguished from patients with PSP and PD by both manual measurement methods and automated volume segmentation using absolute values or ratios.
Assuntos
Doença por Corpos de Lewy , Doença de Parkinson , Paralisia Supranuclear Progressiva , Humanos , Idoso , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/patologia , Doença por Corpos de Lewy/diagnóstico por imagem , Doença por Corpos de Lewy/patologia , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/patologia , Imageamento por Ressonância Magnética/métodos , Atrofia/patologia , Diagnóstico DiferencialRESUMO
BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common dementia type in patients older than 65 years. Its atrophy patterns remain unknown. Its similarities to Parkinson's disease and differences from Alzheimer's disease are subjects of current research. METHODS: The aim of our study was (i) to form a group of patients with DLB (and a control group) and create a 3D MRI data set (ii) to volumetrically analyze the entire brain in these groups, (iii) to evaluate visual and manual metric measurements of the innominate substance for real-time diagnosis, and (iv) to compare our groups and results with the latest literature. We identified 102 patients with diagnosed DLB in our psychiatric and neurophysiological archives. After exclusion, 63 patients with valid 3D data sets remained. We compared them with a control group of 25 patients of equal age and sex distribution. We evaluated the atrophy patterns in both (1) manually and (2) via Fast Surfers segmentation and volumetric calculations. Subgroup analyses were done of the CSF data and quality of 3D T1 data sets. RESULTS: Concordant with the literature, we detected moderate, symmetric atrophy of the hippocampus, entorhinal cortex and amygdala, as well as asymmetric atrophy of the right parahippocampal gyrus in DLB. The caudate nucleus was unaffected in patients with DLB, while all the other measured territories were slightly too moderately atrophied. The area under the curve analysis of the left hippocampus volume ratio (< 3646mm3) revealed optimal 76% sensitivity and 100% specificity (followed by the right hippocampus and left amygdala). The substantia innominata's visual score attained a 51% optimal sensitivity and 84% specificity, and the measured distance 51% optimal sensitivity and 68% specificity in differentiating DLB from our control group. CONCLUSIONS: In contrast to other studies, we observed a caudate nucleus sparing atrophy of the whole brain in patients with DLB. As the caudate nucleus is known to be the last survivor in dopamine-uptake, this could be the result of an overstimulation or compensation mechanism deserving further investigation. Its relative hypertrophy compared to all other brain regions could enable an imaging based identification of patients with DLB via automated segmentation and combined volumetric analysis of the hippocampus and amygdala.
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Doença de Alzheimer , Doença por Corpos de Lewy , Doença de Alzheimer/patologia , Atrofia/patologia , Hipocampo/patologia , Humanos , Doença por Corpos de Lewy/diagnóstico , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: Postoperative delirium is a common complication of cardiac surgery associated with higher morbidity, longer hospital stay, risk of cognitive decline, dementia, and mortality. Geriatric patients, patients undergoing cardiac surgery, and intensive care patients are at a high risk of developing postoperative delirium. Gold standard assessments or biomarkers to predict risk factors for delirium, cognitive decline, and dementia in patients undergoing cardiac surgery are not yet available. METHODS: The FINDERI trial (FINd DElirium RIsk factors) is a prospective, single-center, observational study. In total, 500 patients aged ≥ 50 years undergoing cardiac surgery at the Department of Cardiovascular and Thoracic Surgery of the University of Göttingen Medical Center will be recruited. Our primary aim is to validate a delirium risk assessment in context of cardiac surgery. Our secondary aims are to identify specific preoperative and perioperative factors associated with delirium, cognitive decline, and accelerated dementia after cardiac surgery, and to identify blood-based biomarkers that predict the incidence of postoperative delirium, cognitive decline, or dementia in patients undergoing cardiac surgery. DISCUSSION: This prospective, observational study might help to identify patients at high risk for delirium prior to cardiac surgery, and to identify important biological mechanisms by which cardiac surgery is associated with delirium. The predictive value of a delirium screening questionnaire in cardiac surgery might be revealed. Finally, the identification of specific blood biomarkers might help to predict delirium, cognitive decline, and dementia in patients undergoing cardiac surgery. TRIAL REGISTRATION: Ethics approval for this study was obtained from the IRB of the University of Göttingen Medical Center. The investigators registered this study in the German Clinical Trials Register (DRKS; https://www.drks.de ) (DRKS00025095) on April 19th, 2021.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Disfunção Cognitiva , Delírio , Demência , Idoso , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Disfunção Cognitiva/epidemiologia , Delírio/epidemiologia , Demência/epidemiologia , Humanos , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Fatores de RiscoRESUMO
RsaE is a conserved small regulatory RNA (sRNA) which was previously reported to represent a riboregulator of central carbon flow and other metabolic pathways in Staphylococcus aureus and Bacillus subtilis. Here we show that RsaE contributes to extracellular (e)DNA release and biofilm-matrix switching towards polysaccharide intercellular adhesin (PIA) production in a hypervariable Staphylococcus epidermidis isolate. Transcriptome analysis through differential RNA sequencing (dRNA-seq) in combination with confocal laser scanning microscopy (CLSM) and reporter gene fusions demonstrate that S. epidermidis protein- and PIA-biofilm matrix producers differ with respect to RsaE and metabolic gene expression. RsaE is spatiotemporally expressed within S. epidermidis PIA-mediated biofilms, and its overexpression triggers a PIA biofilm phenotype as well as eDNA release in an S. epidermidis protein biofilm matrix-producing strain background. dRNA-seq and Northern blot analyses revealed RsaE to exist as a major full-length 100-nt transcript and a minor processed species lacking approximately 20 nucleotides at the 5'-end. RsaE processing results in expansion of the mRNA target spectrum. Thus, full-length RsaE interacts with S. epidermidis antiholin-encoding lrgA mRNA, facilitating bacterial lysis and eDNA release. Processed RsaE, however, interacts with the 5'-UTR of icaR and sucCD mRNAs, encoding the icaADBC biofilm operon repressor IcaR and succinyl-CoA synthetase of the tricarboxylic acid (TCA) cycle, respectively. RsaE augments PIA-mediated biofilm matrix production, most likely through activation of icaADBC operon expression via repression of icaR as well as by TCA cycle inhibition and re-programming of staphylococcal central carbon metabolism towards PIA precursor synthesis. Additionally, RsaE supports biofilm formation by mediating the release of eDNA as stabilizing biofilm matrix component. As RsaE itself is heterogeneously expressed within biofilms, we consider this sRNA to function as a factor favoring phenotypic heterogeneity and supporting division of labor in S. epidermidis biofilm communities.
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Matriz Extracelular/genética , Pequeno RNA não Traduzido/metabolismo , Staphylococcus epidermidis/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biofilmes , Matriz Extracelular/fisiologia , Perfilação da Expressão Gênica , Regulação Bacteriana da Expressão Gênica/genética , Óperon/genética , Fenótipo , Polissacarídeos Bacterianos/genética , Polissacarídeos Bacterianos/metabolismo , Pequeno RNA não Traduzido/genética , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/metabolismo , Staphylococcus/genética , Staphylococcus epidermidis/metabolismoRESUMO
BACKGROUND: The creation of functional skeletal muscle via tissue engineering holds great promise without sacrificing healthy donor tissue. Different cell types have been investigated regarding their myogenic differentiation potential under the influence of various media supplemented with growth factors. Yet, most cell cultures include the use of animal sera, which raises safety concerns and might lead to variances in results. Electrospun nanoscaffolds represent suitable matrices for tissue engineering of skeletal muscle, combining both biocompatibility and stability. We therefore aimed to develop a serum-free myogenic differentiation medium for the co-culture of primary myoblasts (Mb) and mesenchymal stromal cells derived from the bone marrow (BMSC) and adipose tissue (ADSC) on electrospun poly-ε-caprolacton (PCL)-collagen I-nanofibers. RESULTS: Rat Mb were co-cultured with rat BMSC (BMSC/Mb) or ADSC (ADSC/Mb) two-dimensionally (2D) as monolayers or three-dimensionally (3D) on aligned PCL-collagen I-nanofibers. Differentiation media contained either AIM V, AIM V and Ultroser® G, DMEM/Ham's F12 and Ultroser® G, or donor horse serum (DHS) as a conventional differentiation medium. In 2D co-culture groups, highest upregulation of myogenic markers could be induced by serum-free medium containing DMEM/Ham's F12 and Ultroser® G (group 3) after 7 days. Alpha actinin skeletal muscle 2 (ACTN2) was upregulated 3.3-fold for ADSC/Mb and 1.7-fold for BMSC/Mb after myogenic induction by group 3 serum-free medium when compared to stimulation with DHS. Myogenin (MYOG) was upregulated 5.2-fold in ADSC/Mb and 2.1-fold in BMSC/Mb. On PCL-collagen I-nanoscaffolds, ADSC showed a higher cell viability compared to BMSC in co-culture with Mb. Myosin heavy chain 2, ACTN2, and MYOG as late myogenic markers, showed higher gene expression after long term stimulation with DHS compared to serum-free stimulation, especially in BMSC/Mb co-cultures. Immunocytochemical staining with myosin heavy chain verified the presence of a contractile apparatus under both serum free and standard differentiation conditions. CONCLUSIONS: In this study, we were able to myogenically differentiate mesenchymal stromal cells with myoblasts on PCL-collagen I-nanoscaffolds in a serum-free medium. Our results show that this setting can be used for skeletal muscle tissue engineering, applicable to future clinical applications since no xenogenous substances were used.
Assuntos
Diferenciação Celular , Técnicas de Cocultura/métodos , Colágeno/metabolismo , Células-Tronco Mesenquimais/citologia , Mioblastos/citologia , Actinina , Animais , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Técnicas de Cocultura/instrumentação , Meios de Cultura Livres de Soro/química , Meios de Cultura Livres de Soro/metabolismo , Células-Tronco Mesenquimais/metabolismo , Desenvolvimento Muscular , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Poliésteres , Ratos , Engenharia Tecidual , Alicerces Teciduais/químicaRESUMO
Previous observations that human amniotic fluid cells (AFC) can be transformed by human adenovirus type 5 (HAdV-5) E1A/E1B oncogenes prompted us to identify the target cells in the AFC population that are susceptible to transformation. Our results demonstrate that one cell type corresponding to mesenchymal stem/stroma cells (hMSCs) can be reproducibly transformed by HAdV-5 E1A/E1B oncogenes as efficiently as primary rodent cultures. HAdV-5 E1-transformed hMSCs exhibit all properties commonly associated with a high grade of oncogenic transformation, including enhanced cell proliferation, anchorage-independent growth, increased growth rate, and high telomerase activity as well as numerical and structural chromosomal aberrations. These data confirm previous work showing that HAdV preferentially transforms cells of mesenchymal origin in rodents. More importantly, they demonstrate for the first time that human cells with stem cell characteristics can be completely transformed by HAdV oncogenes in tissue culture with high efficiency. Our findings strongly support the hypothesis that undifferentiated progenitor cells or cells with stem cell-like properties are highly susceptible targets for HAdV-mediated cell transformation and suggest that virus-associated tumors in humans may originate, at least in part, from infections of these cell types. We expect that primary hMSCs will replace the primary rodent cultures in HAdV viral transformation studies and are confident that these investigations will continue to uncover general principles of viral oncogenesis that can be extended to human DNA tumor viruses as well. IMPORTANCE: It is generally believed that transformation of primary human cells with HAdV-5 E1 oncogenes is very inefficient. However, a few cell lines have been successfully transformed with HAdV-5 E1A and E1B, indicating that there is a certain cell type which is susceptible to HAdV-mediated transformation. Interestingly, all those cell lines have been derived from human embryonic tissue, albeit the exact cell type is not known yet. We show for the first time the successful transformation of primary human mesenchymal stromal cells (hMSCs) by HAdV-5 E1A and E1B. Further, we show upon HAdV-5 E1A and E1B expression that these primary progenitor cells exhibit features of tumor cells and can no longer be differentiated into the adipogenic, chondrogenic, or osteogenic lineage. Hence, primary hMSCs represent a robust and novel model system to elucidate the underlying molecular mechanisms of adenovirus-mediated transformation of multipotent human progenitor cells.
Assuntos
Proteínas E1A de Adenovirus/genética , Proteínas E1B de Adenovirus/genética , Adenovírus Humanos/genética , Transformação Celular Viral , Regulação Neoplásica da Expressão Gênica , Regulação Viral da Expressão Gênica , Células-Tronco Mesenquimais/virologia , Proteínas E1A de Adenovirus/metabolismo , Proteínas E1B de Adenovirus/metabolismo , Adenovírus Humanos/crescimento & desenvolvimento , Adenovírus Humanos/metabolismo , Animais , Linhagem Celular Transformada , Proliferação de Células , Aberrações Cromossômicas , Células Epiteliais/patologia , Células Epiteliais/virologia , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Cariótipo , Lentivirus/genética , Lentivirus/metabolismo , Células-Tronco Mesenquimais/patologia , Oncogenes , Cultura Primária de Células , Ratos , TransfecçãoRESUMO
The therapeutic effect of mesenchymal stromal cells (MSC) in tissue regeneration is based mainly on the secretion of bioactive molecules. Here, we report that the radioprotective effect of mouse bone marrow derived mesenchymal stromal cells (mMSC) can be attributed to extracellular vesicles (EV) released from mMSC. The transplantation of mMSC-derived EV into lethally irradiated mice resulted in long-term survival but no improvement in short-term reconstitution of the recipients. Importantly, the radiation rescue was efficient without additional hematopoietic support. In vitro we show a protection by EV of irradiated hematopoietic stem cells but not progenitor cells using stroma-cell cultures and colony-forming assays. After systemic infusion into lethally irradiated recipients, labeled EV traveled freely through the body reaching the bone marrow within 2 hours. We further show that long-term repopulating Sca-1 positive and c-kit low-positive stem cells were directly targeted by EV leading to long-term survival. Collectively, our data suggest EV as an effective first-line treatment to combat radiation-induced hematopoietic failure which might also be helpful in alleviating myelosuppression due to chemotherapy and toxic drug reaction. We suggest the infusion of MSC-derived EV as efficient and immediate treatment option after irradiation injuries. Stem Cells 2017;35:2379-2389.
Assuntos
Vesículas Extracelulares/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Células-Tronco Mesenquimais/fisiologia , Irradiação Corporal Total , Animais , Transplante de Medula Óssea , Camundongos , Proteínas Proto-Oncogênicas c-kit/metabolismoRESUMO
BACKGROUND: Stroke induces immune alterations such as impaired oxidative burst and reduced release of neutrophil extracellular traps (NETs). We hypothesised that key enzymes of these defence mechanisms may be altered in ischaemic stroke. Therefore, we analysed the intra- and extracellular amounts of myeloperoxidase (MPO) and neutrophil elastase (NE) in patient sera and granulocytes and monocytes. Because the autonomous nervous system is thought to mediate stroke-induced immune alterations, we also studied the influence of stress hormones and acetylcholine on MPO and NE. Rapid recanalization by recombinant tissue plasminogen activator (r-tPA) is the only available treatment for ischaemic stroke besides thrombectomy, and its influence on antibacterial defence mechanisms of granulocytes and monocytes were addressed here. METHODS: Ex vivo: Intracellular and serum MPO and NE were measured on days 0, 1, 3 and 5 post-stroke by either flow cytometry or enzyme-linked immunosorbent assay (ELISA) and compared to controls. In vitro: Blood from healthy donors was incubated with catecholamines, dexamethasone and acetylcholine, and the percentage of NET-producing cells and the area covered by NETs were quantified immunohistochemically. Intra- and extracellular MPO and NE were quantified by flow cytometry or ELISA. Blood samples from healthy donors were incubated with r-tPA, and oxidative burst, phagocytosis, NETosis, cytokine release, MPO and NE were quantified by flow cytometry, ELISA and microscopy. RESULTS: MPO was reduced in granulocytes but increased in sera obtained from stroke patients compared to controls. NE was not altered intracellularly but was elevated in patient sera. The percentage of NET-producing neutrophils was decreased by stress hormones and increased by acetylcholine. Neither intracellular MPO nor NE was altered by hormone treatment; however, adrenaline and acetylcholine induced NE release. r-tPA led to reduced phagocytosis and oxidative burst in granulocytes and monocytes in vitro. NETosis, MPO release and cytokines were not altered, whereas NE release was enhanced by r-tPA. CONCLUSIONS: Intracellular reduction of MPO might be responsible for reduced NETosis in stroke patients. The impact of enhanced MPO and NE serum levels in stroke patients should be addressed in future studies. r-tPA impaired antibacterial defence function in vitro. Therefore, patients who undergo unsuccessful recanalization therapy might be at higher risk for infection, which should be analysed in future investigations. Immune alterations due to r-tPA effects in stroke patients should also be investigated.
Assuntos
Antibacterianos/farmacologia , Armadilhas Extracelulares/fisiologia , Fagócitos/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/uso terapêutico , Acetilcolina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Isquemia Encefálica/complicações , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Líquido Extracelular/efeitos dos fármacos , Líquido Extracelular/metabolismo , Armadilhas Extracelulares/efeitos dos fármacos , Feminino , Granulócitos/efeitos dos fármacos , Granulócitos/metabolismo , Humanos , Elastase de Leucócito/metabolismo , Masculino , Pessoa de Meia-Idade , Neurotransmissores/metabolismo , Peroxidase/metabolismo , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologiaRESUMO
Background There is evidence for two different types and/or sources of mental illness stigma, namely the display of psychiatric symptoms and the use of psychiatric service institutions. However, no current study has compared the two. Furthermore, gaps exist in our knowledge of both types of stigma. Little is known about the perceived stigma of specific psychiatric service treatment environments, for instance forensic settings. In addition, systematic research on stigma attached to symptoms of personality disorders in the general population is scarce, and for borderline personality disorder, nonexistent. Methods We conducted a representative survey of the general population (N = 2207) in the canton of Basel-Stadt, Switzerland. Participants were asked to read a vignette depicting either the psychiatric symptoms of a fictitious character or a psychiatric service institution to which the character had been admitted, and indicate desired social distance (an indicator for stigma). Type of symptoms, type of psychiatric service, dangerousness, and gender were systematically varied between vignettes. Findings Desired social distance was significantly lower in relation to psychiatric service use than to psychiatric symptoms. Overall, symptoms of alcohol dependency, behavior endangering others, and the fictitious character's being male tend to increase stigmatization. Interestingly, the character's being hospitalized in a psychiatric unit at a general hospital and also respondent familiarity with psychiatric services tend to decrease stigmatization. Interpretation Familiarity of the general population with psychiatric patients should be increased. Furthermore, treatment in psychiatric units located within general hospitals should be promoted, as such treatment is associated with decreased stigma.
Assuntos
Serviços de Saúde/estatística & dados numéricos , Transtornos Mentais/psicologia , Transtornos Mentais/terapia , Distância Psicológica , Estigma Social , Adolescente , Adulto , Feminino , Inquéritos Epidemiológicos , Humanos , Classificação Internacional de Doenças , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estereotipagem , Suíça , Adulto JovemRESUMO
Pathological gambling is defined as inappropriate, persistent, and maladaptive gambling behaviour. It is a non-pharmacological addiction classified as an impulse control disorder. However, pathological gambling has been associated with dopamine agonist use. Here we report of a 28-year-old man with a first major depressive episode and a post-traumatic stress disorder who has been treated with a combination of the serotonine/noradrenaline reuptake inhibitor duloxetine and the tricyclic antidepressant maprotiline. The administration of antipsychotic flupentixole (up to 7 mg) turned this slight online poker gambler into an excessive gambler. Only after the discontinuation of the antidopaminergic agents and the switch to bupropion did this gambling behaviour stop which suggests a causal relationship between dopamine antagonists and pathological gambling.
Assuntos
Comportamento Aditivo/induzido quimicamente , Antagonistas de Dopamina/efeitos adversos , Flupentixol/efeitos adversos , Jogo de Azar/induzido quimicamente , Adulto , Comportamento Aditivo/psicologia , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/tratamento farmacológico , Antagonistas de Dopamina/administração & dosagem , Flupentixol/administração & dosagem , Jogo de Azar/psicologia , Humanos , Masculino , Transtornos de Estresse Pós-Traumáticos/complicações , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológicoRESUMO
Recombinant adeno-associated virus (AAV) vectors are the leading delivery vehicle used for in vivo gene therapies. Anti-AAV antibodies (AAV Abs) can interact with the viral capsid component of an AAV-based gene therapy (GT). Therefore, patients with preexisting AAV Abs (seropositive patients) are often excluded from GT trials to prevent treatment of patients who are unlikely to benefit1 or may have a higher risk for adverse events outweighing treatment benefits. On the contrary, unnecessary exclusion of patients with high unmet medical need should be avoided. Instead, a risk-benefit assessment that weighs the potential risks due to seropositivity vs. severity of disease and available treatment options, should drive the decision if patient selection is required. Assays for patient selection must be validated according to their intended use following national regulations/standards for diagnostic assays in appropriate laboratories. In this review, we summarize the current process of patient selection, including assay cutoff criteria and related assay validation approaches. We further provide considerations on regulatory requirements for the development of in vitro diagnostic tests supporting market authorization of a corresponding GT.
RESUMO
Human activities are accelerating rates of biological invasions and climate-driven range expansions globally, yet we understand little of how genomic processes facilitate the invasion process. Although most of the literature has focused on underlying phenotypic correlates of invasiveness, advances in genomic technologies are showing a strong link between genomic variation and invasion success. Here, we consider the ability of genomic tools and technologies to (i) inform mechanistic understanding of biological invasions and (ii) solve real-world issues in predicting and managing biological invasions. For both, we examine the current state of the field and discuss how genomics can be leveraged in the future. In addition, we make recommendations pertinent to broader research issues, such as data sovereignty, metadata standards, collaboration, and science communication best practices that will require concerted efforts from the global invasion genomics community.
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Genômica , Espécies Introduzidas , Humanos , ClimaRESUMO
Inorganic-organic composite implant materials mimicking the environment of bone are promising applications to meet the increasing demands on biomaterials for bone regeneration caused by extended life spans and the concomitant increase of bone treatments. Besides collagen type I (Col-I) glycosaminoglycans (GAG), such as hyaluronan, are important components of the bone extracellular matrix (ECM). Sulfated GAGs are potential stimulators of bone anabolic activity, as they are involved in the recruitment of mesenchymal stromal cells (MSCs) to the site of bone formation and support differentiation to osteoblasts. Nevertheless, no consecutive data is currently available about the interaction of hyaluronan or sulfated hyaluronan derivatives with hMSCs and the molecular processes being consequently regulated. We applied quantitative proteomics to investigate the influence of artificial ECM composed of Col-I and hyaluronan (Hya) or sulfated hyaluronan (HyaS3) on the molecular adaptation of osteogenic-differentiated human MSCs (hMSCs). Of the 1,370 quantified proteins, the expression of 4-11% was altered due to both aECM-combinations. Our results indicate that HyaS3 enhanced multiple cell functions, including cell-matrix-interaction, cell-signaling, endocytosis, and differentiation. In conclusion, this study provides fundamental insights into regulative cellular responses associated with HyaS3 and Hya as components of aECM and underlines the potential of HyaS3 as a promising implant-coating-material.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Matriz Extracelular , Ácido Hialurônico , Células-Tronco Mesenquimais , Adulto , Materiais Biocompatíveis/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colágeno Tipo I/metabolismo , Endocitose/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Glicosaminoglicanos/química , Glicosaminoglicanos/metabolismo , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/metabolismo , Ácido Hialurônico/farmacologia , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Proteômica , Transdução de Sinais/efeitos dos fármacos , Sulfatos/químicaRESUMO
The purpose of this study was to analyze the influence of E- and P-selectins on the migratory pattern of magnetically labeled multipotent mesenchymal stromal cells (MSCs) in mice using magnetic resonance imaging (MRI). Murine MSCs were labeled with fluorescent iron oxide microparticles and carboxyfluorescein succinidyl ester (CFSE). Expression of common MSC markers, CD44, CD90, CD105, and Sca-1, as well as of selectin ligands, CD15s and CD162, was assessed using flow cytometry and immunocytochemistry. Labeled MSCs were injected into E-/P-selectin-deficient and wild-type mice applying doses of 5 × 10(4) cells intracardially, 1 × 10(6) cells intravenously, and 5 × 10(6) cells intraperitoneally. After cell administration, mice underwent MRI repeatedly and histologic evaluation after 7 days. The results demonstrate that magnetically labeled murine MSCs retain their expression of the above-mentioned surface markers and their ability to interact with P-selectin. Furthermore, MRI examinations and histologic analysis revealed that E-/P-selectin deficiency in mice significantly alters the distribution of labeled MSCs after cell injection via different routes.
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Selectina E/metabolismo , Imageamento por Ressonância Magnética/métodos , Células-Tronco Mesenquimais/metabolismo , Selectina-P/metabolismo , Animais , Células Cultivadas , Citometria de Fluxo , Imuno-Histoquímica , Ferro/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
In recent years, lithium has proved an effective augmentation strategy of antidepressants in both acute and treatment-resistant depression. Neuroprotective and procognitive effects of lithium have been evidenced. Brain-derived neurotrophic factor (BDNF) has been shown to play a key role in the pathophysiology of several neurological and psychiatric disorders. The BDNF hypothesis of depression postulates that a loss of BDNF is directly involved in the pathophysiology of depression, and its restoration may underlie the therapeutic efficacy of antidepressant treatments. Brain-derived neurotrophic factor serum concentrations were measured in a total of 83 acutely depressed patients before and after 4 weeks of lithium augmentation. A significant BDNF increase has been found during treatment (F2,81 = 5.04, P < 0.05). Brain-derived neurotrophic factor concentrations at baseline correlated negatively with relative Hamilton Depression Scale change after treatment with lithium (n = 83; r = -0.23; P < 0.05). This is the first study showing that lithium augmentation of an antidepressant strategy can increase BDNF serum concentrations. Our study replicates previous findings showing that serum BDNF levels in patients with depressive episodes increase during effective antidepressant treatment. Further studies are needed to separate specific effects of different antidepressants on BDNF concentration and address potential BDNF downstream mechanisms.
Assuntos
Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/sangue , Transtorno Depressivo Maior/tratamento farmacológico , Carbonato de Lítio/uso terapêutico , Doença Aguda , Adulto , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Resistente a Tratamento/sangue , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/fisiopatologia , Quimioterapia Combinada , Feminino , Humanos , Carbonato de Lítio/administração & dosagem , Carbonato de Lítio/farmacologia , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Resultado do TratamentoRESUMO
Mesenchymal stromal cells (MSCs) have been shown to display a considerable therapeutic potential in cellular therapies. However, harmful adipogenic maldifferentiation of transplanted MSCs may seriously threaten the success of this therapeutic approach. We have previously demonstrated that using platelet lysate (PL) instead of widely used fetal calf serum (FCS) diminished lipid accumulation in adipogenically stimulated human MSCs and identified, among others, lipocalin-type prostaglandin D2 synthase (L-PGDS) as a gene suppressed in PL-supplemented MSCs. Here, we investigated the role of PL and putatively pro-adipogenic L-PGDS in human MSC adipogenesis. Next to strongly reduced levels of L-PGDS we show that PL-supplemented MSCs display markedly decreased expression of adipogenic master regulators and differentiation markers, both before and after induction of adipocyte differentiation. The low adipogenic differentiation capability of PL-supplemented MSCs could be partially restored by exogenous addition of L-PGDS protein. Conversely, siRNA-mediated downregulation of L-PGDS in FCS-supplemented MSCs profoundly reduced adipocyte differentiation. In contrast, inhibiting endogenous prostaglandin synthesis by aspirin did not reduce differentiation, suggesting that a mechanism such as lipid shuttling but not the prostaglandin D2 synthase activity of L-PGDS is critical for adipogenesis. Our data demonstrate that L-PGDS is a novel pro-adipogenic factor in human MSCs which might be of relevance in adipocyte metabolism and disease. L-PGDS gene expression is a potential quality marker for human MSCs, as it might predict unwanted adipogenic differentiation after MSC transplantation.
Assuntos
Adipócitos/citologia , Plaquetas/metabolismo , Diferenciação Celular , Oxirredutases Intramoleculares/metabolismo , Lipocalinas/metabolismo , Células-Tronco Mesenquimais/citologia , Adipócitos/metabolismo , Adipogenia , Células Cultivadas , Humanos , Oxirredutases Intramoleculares/antagonistas & inibidores , Oxirredutases Intramoleculares/genética , Lipocalinas/antagonistas & inibidores , Lipocalinas/genética , Células-Tronco Mesenquimais/metabolismo , RNA Interferente Pequeno/genéticaRESUMO
Purpose: Anti-vascular endothelial growth factor (anti-VEGF) therapies, which attenuate the capacity of VEGF to bind to VEGF receptors, are standard-of-care options for various retinal disorders that are characterized by pathologic retinal angiogenesis and vascular permeability. Multiple receptors and ligands have also been reported as being involved in these pathways, including angiopoietin-1 (ANG1) and angiopoietin-2 (ANG2). Methods: Electrochemiluminescence immunoassays were used to detect human VEGF (hVEGF), as well as rabbit ANG2 and basic fibroblast growth factor protein levels in vitreous samples derived from a study evaluating the efficacy of the anti-VEGF agents ranibizumab, aflibercept, and brolucizumab in an hVEGF165-induced rabbit retinal vascular hyperpermeability model. Results: hVEGF was completely suppressed in rabbit vitreous after anti-VEGF treatment for 28 days. ANG2 protein in vitreous and ANGPT2 mRNA in retina tissue were similarly suppressed, although the anti-VEGF agents do not directly bind to ANG2. Aflibercept demonstrated the greatest inhibitory effect in ANG2 levels in vitreous, which correlated with strong, durable suppression of intraocular hVEGF levels. Conclusions: This study explored the effects of anti-VEGF therapies beyond direct binding of VEGF by evaluating protein levels and the expression of target genes involved in angiogenesis and associated molecular mechanisms in the rabbit retina and choroid. Translational Relevance: In vivo data suggest that anti-VEGF agents currently used for the treatment of retinal diseases could provide beneficial effects beyond direct binding of VEGF, including suppression of ANG2 protein and ANGPT2 mRNA.
Assuntos
Angiopoietina-2 , Fator A de Crescimento do Endotélio Vascular , Animais , Coelhos , Humanos , Fator A de Crescimento do Endotélio Vascular/genética , Angiopoietina-2/genética , Angiopoietina-2/metabolismo , Fatores de Crescimento do Endotélio Vascular , Receptores de Fatores de Crescimento do Endotélio Vascular , Neovascularização Patológica , RNA Mensageiro/metabolismoRESUMO
Hemophilia A, a single gene disorder leading to deficient Factor VIII (FVIII), is a suitable candidate for gene therapy. The aspiration is for single administration of a genetic therapy that would allow the production of endogenous FVIII sufficient to restore hemostasis and other biological processes. This would potentially result in reliable protection from bleeding and its associated physical and emotional impacts. Gene therapy offers the possibility of a clinically relevant improvement in disease phenotype and transformational improvement in quality of life, including an opportunity to engage in physical activities more confidently. Gene therapy products for hemophilia A in advanced clinical development use adeno-associated viral (AAV) vectors and a codon-optimized B-domain deleted FVIII transgene. However, the different AAV-based gene therapies have distinct design features, such as choice of vector capsid, enhancer and promoter regions, FVIII transgene sequence and manufacturing processes. These, in turn, impact patient eligibility, safety and efficacy. Ideally, gene therapy technology for hemophilia A should offer bleed protection, durable FVIII expression, broad eligibility and limited response variability between patients, and long-term safety. However, several limitations and challenges must be overcome. Here, we introduce the characteristics of the BAY 2599023 (AAVhu37.hFVIIIco, DTX 201) gene therapy product, including the low prevalence in the general population of anti-AAV-hu37 antibodies, as well as other gene therapy AAV products and approaches. We will examine how these can potentially meet the challenges of gene therapy, with the ultimate aim of improving the lives of patients with hemophilia A.
Assuntos
Hemofilia A , Animais , Humanos , Dependovirus/genética , Terapia Genética , Hemofilia A/genética , Hemofilia A/terapia , Qualidade de VidaRESUMO
BACKGROUND AND PURPOSE: The diagnosis of Dementia with Lewy Bodies (DLB) is challenging due to various clinical presentations and clinical and neuropathological features that overlap with Alzheimer's disease (AD). The use of 18 F-Fluorodeoxyglucose-PET (18 F-FDG-PET) can be limited due to similar patterns in DLB and AD. However, metabolism in the posterior cingulate cortex is known to be relatively preserved in DLB and visual assessment of the "cingulate island sign" became a helpful tool in the analysis of 18F-FDG-PET. The aim of this study was the evaluation of visual and semiquantitative 18F-FDG-PET analyses in the diagnosis of DLB and the differentiation to AD as well as its relation to other dementia biomarkers. METHODS: This retrospective study comprises 81 patients with a clinical diagnosis of DLB or AD that underwent 18 F-FDG-PET/CT. PET scans were analyzed visually and semiquantitatively and results were compared to clinical data, cerebrospinal fluid results, dopamine transporter scintigraphy, and 18F-Florbetaben-PET. Furthermore, different cingulate island ratios were calculated to analyze their diagnostic accuracy. RESULTS: Visual assessment of 18F-FDG-PET showed an accuracy of 62%-77% in differentiating between DLB and AD. Standard uptake values were significantly lower in the primary visual cortex and the lateral occipital cortex of DLB patients compared to AD patients. The cingulate island ratio was significantly higher in the DLB group compared to the AD group and the ratio posterior cingulate cortex to visual cortex plus lateral occipital cortex showed the highest diagnostic accuracy to discriminate between DLB and AD at 81%. CONCLUSIONS: Semiquantitative 18F-FDG-PET imaging and especially the use of an optimized cingulate island ratio are valuable tools to differentiate between DLB and AD.