RESUMEN
A paradigm shift in research culture is required to ease perceived tensions between autistic people and the biomedical research community. As a group of autistic and non-autistic scientists and stakeholders, we contend that through participatory research, we can reject a deficit-based conceptualization of autism while building a shared vision for a neurodiversity-affirmative biomedical research paradigm.
Asunto(s)
Trastorno Autístico , Investigación Biomédica , Humanos , Investigación Biomédica/ética , Conducta , Investigación Participativa Basada en la ComunidadRESUMEN
BACKGROUND: Increasing recognition of autism is reflected in the growing awareness of autistic health care providers. Regulatory bodies including the UK General Medical Council and the UK Medical Schools Council have published guidance fostering inclusion. Whilst many autistic doctors and students are thriving, many may not disclose their diagnosis unless difficulties arise, which perpetuates stereotypes. No studies have explored the experiences of autistic medical students. We aimed to do this. METHODS: This was an interpretive phenomenological study. Autistic medical students were recruited using Facebook announcements. Participants underwent audio-recorded, loosely structured interviews. Recordings were transcribed verbatim and underwent an interpretive phenomenological analysis. RESULTS: Five participated from five different UK medical schools. Constructed themes included: Autistic profiles and stereotypes-'I'm a lot better with patients than I am with my peers, with staff, which is hard for a lot of people to understand'; sensory processing and the learning environment-'noises really hurt my ears It actually hurts'; me, myself and masking-'so, medicine's hard. But I'm also studying myself and I'm figuring myself out and that degree is harder'; the social world-'I always feel like I'm watching my back'; and navigating the system-'[they say] "but you're going to be a doctor one day, so you need to get used to it"'. CONCLUSION: Participants longed for understanding and support from their medical schools. They reported experiences of isolation, bullying and anxiety. Most felt themselves to be victims of the system, whereby they were expected to adapt themselves in order to appear non-autistic. When participants reported not coping due to being autistic, most were advised to 'take time out'. None were offered personalised adjustments to their learning environment. All reported strengths associated with being autistic. This supports the assertion that autistic people can be safe, effective and skilled doctors.
Asunto(s)
Trastorno Autístico , Estudiantes de Medicina , Humanos , Emociones , Ansiedad , AprendizajeRESUMEN
CBL is rapidly phosphorylated upon insulin receptor activation. Mice whole body CBL depletion improved insulin sensitivity and glucose clearance; however, the precise mechanisms remain unknown. We depleted either CBL or its associated protein SORBS1/CAP independently in myocytes and assessed mitochondrial function and metabolism compared to control cells. CBL- and CAP-depleted cells showed increased mitochondrial mass with greater proton leak. Mitochondrial respiratory complex I activity and assembly into respirasomes were reduced. Proteome profiling revealed alterations in proteins involved in glycolysis and fatty acid degradation. Our findings demonstrate CBL/CAP pathway couples insulin signaling to efficient mitochondrial respiratory function and metabolism in muscle.
Asunto(s)
Resistencia a la Insulina , Proteínas Proto-Oncogénicas c-cbl , Animales , Ratones , Metabolismo Energético , Insulina/metabolismo , Mitocondrias/metabolismo , Mitocondrias Musculares/metabolismo , Células Musculares/metabolismo , Proteínas Proto-Oncogénicas c-cbl/metabolismo , Respiración de la CélulaRESUMEN
The purpose of the current qualitative descriptive study was to describe the experiences of women who have endured intimate partner abuse using the theoretical framework of posttraumatic growth (PTG). Women (N = 14) who reported emotional and/or physical abuse by their male partners were interviewed. Five themes were identified: Acknowledging the Abusive Relationship; Fear of Him: Threats, Control, Pain, and Isolation; Accepting Support: Grabbing the Life Preserver; Rediscovering Myself: Digging Deep; and Appreciating Life and Helping Others. Findings have practical implications for nurses who are in pivotal positions to educate and influence others about the possibility of PTG following partner abuse. Nurses can help women find their way through this trauma and teach others about coping, healing, and recovery. [Journal of Psychosocial Nursing and Mental Health Services, 61(8), 34-41.].
Asunto(s)
Violencia de Pareja , Crecimiento Psicológico Postraumático , Maltrato Conyugal , Humanos , Masculino , Femenino , Violencia de Pareja/psicología , Maltrato Conyugal/psicología , Emociones , Adaptación PsicológicaRESUMEN
Autistic psychiatrists bring strengths and values to the workforce and ask to be acknowledged and supported as part of the Royal College of Psychiatrists' CIRCLE values and Equality Action Plan. Courage and collaboration are required to jointly learn and innovate, promoting well-being, resilience and excellence for autistic doctors.
Asunto(s)
Trastorno Autístico , Médicos , Psiquiatría , Trastorno Autístico/terapia , Humanos , Recursos HumanosRESUMEN
BACKGROUND: Rainbow trout (Oncorhynchus mykiss) is a salmonid species with a complex life-history. Wild populations are naturally divided into freshwater residents and sea-run migrants. Migrants undergo an energy-demanding adaptation for life in seawater, known as smoltification, while freshwater residents display these changes in an attenuated magnitude and rate. Despite this, in seawater rainbow trout farming all fish are transferred to seawater. Under these circumstances, weeks after seawater transfer, a significant portion of the fish die (around 10%) or experience growth stunting (GS; around 10%), which represents an important profitability and welfare issue. The underlying causes leading to GS in seawater-transferred rainbow trout remain unknown. In this study, we aimed at characterising the GS phenotype in seawater-transferred rainbow trout using untargeted and targeted approaches. To this end, the liver proteome (LC-MS/MS) and lipidome (LC-MS) of GS and fast-growing phenotypes were profiled to identify molecules and processes that are characteristic of the GS phenotype. Moreover, the transcription, abundance or activity of key proteins and hormones related to osmoregulation (Gill Na+, K + -ATPase activity), growth (plasma IGF-I, and liver igf1, igfbp1b, ghr1 and ctsl) and stress (plasma cortisol) were measured using targeted approaches. RESULTS: No differences in Gill Na+, K + -ATPase activity and plasma cortisol were detected between the two groups. However, a significant downregulation in plasma IGF-I and liver igf1 transcription pointed at this growth factor as an important pathomechanism for GS. Changes in the liver proteome revealed reactive-oxygen-species-mediated endoplasmic reticulum stress as a key mechanism underlying the GS phenotype. From the lipidomic analysis, key observations include a reduction in triacylglycerols and elevated amounts of cardiolipins, a characteristic lipid class associated with oxidative stress, in GS phenotype. CONCLUSION: While the triggers to the activation of endoplasmic reticulum stress are still unknown, data from this study point towards a nutritional deficiency as an underlying driver of this phenotype.
Asunto(s)
Oncorhynchus mykiss , Animales , Cromatografía Liquida , Estrés del Retículo Endoplásmico , Trastornos del Crecimiento , Oncorhynchus mykiss/genética , Agua de Mar , Espectrometría de Masas en TándemRESUMEN
BACKGROUND/AIMS: The use of novel cryo-additive agents to increase cell viability post-cryopreservation is paramount to improve future cell based-therapy treatments. We aimed to establish the Human Leukemia (HL-60) cells lipidomic and biological patterns when cryo-preserved in DMSO alone and with 300 µM Nigerose (Nig), 200 µM Salidroside (Sal) or a combination of Nig (150 µM) and Sal (100 µM). METHODS: HL-60 cells were pre-incubated with Nig/Sal prior, during and post cryopreservation, and subjected to global lipidomic analysis. Malondialdeyhde (MDA), released lactate dehydrogenase (LDH) and reactive oxygen scavenger (ROS) measurements were also carried out to evaluate levels of lipid peroxidation and cytotoxicity. RESULTS: Cryopreserving HL-60 cells in DMSO with Nig and Sal provided optimal protection against unsaturated fatty acid oxidation. Post-thaw, cellular phospholipids and mitochondrial cardiolipins were increased by Nig/Sal as the ratio of unsaturated to saturated fatty acids 2.08 +/- 0.03 and 0.95 +/- 0.09 folds respectively in comparison to cells cryopreserved in DMSO alone (0.49 +/- 0.05 and 0.86 +/- 0.10 folds). HL-60 lipid peroxidation levels in the presence of DMSO + Nig and Sal combined were significantly reduced relative to pre-cryopreservation levels (10.91 +/- 2.13 nmole) compared to DMSO (17.1 +/- 3.96 nmole). DMSO + Nig/Sal combined also significantly reduced cell cytotoxicity post-thaw (0.0128 +/- 0.00182 mU/mL) in comparison to DMSO (0.0164 +/- 0.00126 mU/mL). The combination of Nig/Sal also reduced significantly ROS levels to the levels of prior cryopreservation of HL-60. CONCLUSION: Overall, the establishment of the cryopreserved HL-60 cells lipidomic and the corresponding biological profiles showed an improved cryo-formulation in the presence of DMSO with the Nig/Sal combination by protecting the, mitochondrial inner membrane, unsaturated fatty acid components (i. e. Cardiolipins) and total phospholipids.
Asunto(s)
Disacáridos/química , Leucemia/metabolismo , Mitocondrias/metabolismo , Cardiolipinas/metabolismo , Supervivencia Celular/efectos de los fármacos , Criopreservación , Dimetilsulfóxido/farmacología , Disacáridos/farmacología , Glucósidos/farmacología , Células HL-60 , Humanos , Peroxidación de Lípido/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , Fenoles/farmacologíaRESUMEN
Mutations in glucocerebrosidase (GBA) are the most prevalent genetic risk factor for Lewy body disorders (LBD)-collectively Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies. Despite this genetic association, it remains unclear how GBA mutations increase susceptibility to develop LBD. We investigated relationships between LBD-specific glucocerebrosidase deficits, GBA-related pathways, and α-synuclein levels in brain tissue from LBD and controls, with and without GBA mutations. We show that LBD is characterised by altered sphingolipid metabolism with prominent elevation of ceramide species, regardless of GBA mutations. Since extracellular vesicles (EV) could be involved in LBD pathogenesis by spreading disease-linked lipids and proteins, we investigated EV derived from post-mortem cerebrospinal fluid (CSF) and brain tissue from GBA mutation carriers and non-carriers. EV purified from LBD CSF and frontal cortex were heavily loaded with ceramides and neurodegeneration-linked proteins including alpha-synuclein and tau. Our in vitro studies demonstrate that LBD EV constitute a "pathological package" capable of inducing aggregation of wild-type alpha-synuclein, mediated through a combination of alpha-synuclein-ceramide interaction and the presence of pathological forms of alpha-synuclein. Together, our findings indicate that abnormalities in ceramide metabolism are a feature of LBD, constituting a promising source of biomarkers, and that GBA mutations likely accelerate the pathological process occurring in sporadic LBD through endolysosomal deficiency.
Asunto(s)
Ceramidas/metabolismo , Vesículas Extracelulares/metabolismo , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , alfa-Sinucleína/metabolismo , Glucosilceramidasa/genética , Humanos , Mutación , Trastornos Parkinsonianos/genética , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/metabolismoRESUMEN
BACKGROUND: There is little evidence to guide management of patients with acute leukemia and intracranial hemorrhage (ICH). Predictors of long-term outcome following ICH are unknown. STUDY DESIGN AND METHODS: This study included adult patients with acute leukemia and ICH over an 8-year period. The primary outcome was data regarding 90-day mortality. Secondary outcomes included data related to the proportion of patients receiving post-remission therapy and predictors of 90-day mortality. RESULTS: ICH occurred in 101 patients; 12 patients died within 72 hours. For the 89 others, 90-day mortality was 40%. Of 43 patients who received induction, 30 achieved remission and 26 received post-remission therapy. Older age (p = 0.03) and higher white count (p = 0.02) at the time of ICH were predictive of inferior survival. During 90-day follow-up, median platelet count was 37 x 109 /L (0-1526 x 109 /L). Lower platelet count during follow-up was predictive of 90-day mortality (p = <0.01). Twenty-one percent of platelet transfusions were provided when the platelet count was less than 10 x 109 /L, 54% between 10 and 29 x 109 /L, and 25% greater than 30 x 109 /L. New or progressive ICH occurred in 23 patients. There was no difference in the median platelet transfusion trigger between patients who had new or progressive ICH and those who did not. CONCLUSION: In patients with acute leukemia, survival following ICH is poor. Older age and higher white count is associated with increased mortality, perhaps reflecting higher risk disease. Following ICH in acute leukemia platelet transfusions do not appear to alter the risk of progressive bleeding or mortality.
Asunto(s)
Hemorragias Intracraneales/terapia , Leucemia/terapia , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Transfusión de Plaquetas/métodos , Estudios Retrospectivos , Trombocitopenia/terapia , Adulto JovenRESUMEN
Triple-negative breast cancer (TNBC), the deadliest form of this disease, lacks a targeted therapy. TNBC tumors that fail to respond to chemotherapy are characterized by a repressed IFN/signal transducer and activator of transcription (IFN/STAT) gene signature and are often enriched for cancer stem cells (CSCs). We have found that human mammary epithelial cells that undergo an epithelial-to-mesenchymal transition (EMT) following transformation acquire CSC properties. These mesenchymal/CSCs have a significantly repressed IFN/STAT gene expression signature and an enhanced ability to migrate and form tumor spheres. Treatment with IFN-beta (IFN-ß) led to a less aggressive epithelial/non-CSC-like state, with repressed expression of mesenchymal proteins (VIMENTIN, SLUG), reduced migration and tumor sphere formation, and reexpression of CD24 (a surface marker for non-CSCs), concomitant with an epithelium-like morphology. The CSC-like properties were correlated with high levels of unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3), which was previously linked to resistance to DNA damage. Inhibiting the expression of IRF9 (the DNA-binding component of U-ISGF3) reduced the migration of mesenchymal/CSCs. Here we report a positive translational role for IFN-ß, as gene expression profiling of patient-derived TNBC tumors demonstrates that an IFN-ß metagene signature correlates with improved patient survival, an immune response linked with tumor-infiltrating lymphocytes (TILs), and a repressed CSC metagene signature. Taken together, our findings indicate that repressed IFN signaling in TNBCs with CSC-like properties is due to high levels of U-ISGF3 and that treatment with IFN-ß reduces CSC properties, suggesting a therapeutic strategy to treat drug-resistant, highly aggressive TNBC tumors.
Asunto(s)
Transición Epitelial-Mesenquimal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Interferón beta/farmacología , Proteínas de Neoplasias/biosíntesis , Células Madre Neoplásicas/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Línea Celular Tumoral , Femenino , Humanos , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/patología , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
PURPOSE: To describe vicarious posttraumatic growth in U.S. military nurses who served in the Iraq and Afghanistan wars. DESIGN: A cross-sectional descriptive design was used. METHODS: Respondents were asked to complete the Posttraumatic Growth Inventory (PTGI), Core Beliefs Inventory (CBI), and six open-ended write-in questions as an electronic survey. FINDINGS: Appreciation of life and Personal strength were the strongest dimensions on the PTGI. This was also evident in participant responses to the open-ended questions. The five dimensions of the PTGI were significantly correlated, indicating as growth increased in one dimension, growth increased in all dimensions. The CBI showed moderate to strong positive correlations with all items. Thus, the relationship between the total PTGI scores and the total CBI scores showed a strong, positive correlation, which indicated higher overall core belief scores associated with more growth in total PTGI scores. CONCLUSIONS: This study provided initial evidence that some nurses who served in the Iraq and Afghanistan wars experienced posttraumatic growth. While healthcare providers need to be educated about their vulnerability when exposed to trauma, they also need to be aware of potential growth when caring for casualties. CLINICAL RELEVANCE: Nurses preparing to serve in war, as well as those returning, need to pay attention to their physical, psychological, emotional, and spiritual health. Following return from war deployment, the military services need to take deliberate and careful measures to ensure that no returning personnel "fall through the cracks" in getting the help they need.
Asunto(s)
Despliegue Militar/psicología , Enfermería Militar , Personal Militar/psicología , Crecimiento Psicológico Postraumático , Adulto , Campaña Afgana 2001- , Anciano , Estudios Transversales , Femenino , Humanos , Guerra de Irak 2003-2011 , Masculino , Persona de Mediana Edad , Personal Militar/estadística & datos numéricos , Encuestas y Cuestionarios , Estados UnidosRESUMEN
BACKGROUND: Highly aggressive, metastatic and therapeutically resistant triple-negative breast cancers (TNBCs) are often enriched for cancer stem cells (CSC). Cytokines within the breast tumor microenvironment (TME) influence the CSC state by regulating tumor cell differentiation programs. Two prevalent breast TME cytokines are oncostatin-M (OSM) and interferon-ß (IFN-ß). OSM is a member of the IL-6 family of cytokines and can drive the de-differentiation of TNBC cells to a highly aggressive CSC state. Conversely, IFN-ß induces the differentiation of TNBC, resulting in the repression of CSC properties. Here, we assess how these breast TME cytokines influence CSC plasticity and clinical outcome. METHODS: Using transformed human mammary epithelial cell (HMEC) and TNBC cell models, we assessed the CSC markers and properties following exposure to OSM and/or IFN-ß. CSC markers included CD24, CD44, and SNAIL; CSC properties included tumor sphere formation, migratory capacity, and tumor initiation. RESULTS: There are three major findings from our study. First, exposure of purified, non-CSC to IFN-ß prevents OSM-mediated CD44 and SNAIL expression and represses tumor sphere formation and migratory capacity. Second, during OSM-induced de-differentiation, OSM represses endogenous IFN-ß mRNA expression and autocrine/paracrine IFN-ß signaling. Restoring IFN-ß signaling to OSM-driven CSC re-engages IFN-ß-mediated differentiation by repressing OSM/STAT3/SMAD3-mediated SNAIL expression, tumor initiation, and growth. Finally, the therapeutic use of IFN-ß to treat OSM-driven tumors significantly suppresses tumor growth. CONCLUSIONS: Our findings suggest that the levels of IFN-ß and OSM in TNBC dictate the abundance of cells with a CSC phenotype. Indeed, TNBCs with elevated IFN-ß signaling have repressed CSC properties and a better clinical outcome. Conversely, TNBCs with elevated OSM signaling have a worse clinical outcome. Likewise, since OSM suppresses IFN-ß expression and signaling, our studies suggest that strategies to limit OSM signaling or activate IFN-ß signaling will disengage the de-differentiation programs responsible for the aggressiveness of TNBCs.
Asunto(s)
Interferón beta/farmacología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Oncostatina M/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Línea Celular Tumoral , Citocinas/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Transducción de Señal/efectos de los fármacos , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Acylated amino acids function as important components of the cellular membrane in some bacteria. Biosynthesis is initiated by the N-acylation of the amino acid, and this is followed by subsequent O-acylation of the acylated molecule, resulting in the production of the mature diacylated amino acid lipid. In this study, we use both genetics and liquid chromatography-mass spectrometry (LC-MS) to characterize the biosynthesis and function of a diacylated glycine lipid (GL) species produced in Bacteroides thetaiotaomicron We, and others, have previously reported the identification of a gene, named glsB in this study, that encodes an N-acyltransferase activity responsible for the production of a monoacylated glycine called N-acyl-3-hydroxy-palmitoyl glycine (or commendamide). In all of the Bacteroidales genomes sequenced so far, the glsB gene is located immediately downstream from a gene, named glsA, that is also predicted to encode a protein with acyltransferase activity. We use LC-MS to show that the coexpression of glsB and glsA results in the production of GL in Escherichia coli We constructed a deletion mutant of the glsB gene in B. thetaiotaomicron, and we confirm that glsB is required for the production of GL in B. thetaiotaomicron Moreover, we show that glsB is important for the ability of B. thetaiotaomicron to adapt to stress and colonize the mammalian gut. Therefore, this report describes the genetic requirements for the biosynthesis of GL, a diacylated amino acid species that contributes to fitness in the human gut bacterium B. thetaiotaomicronIMPORTANCE The gut microbiome has an important role in both health and disease of the host. The mammalian gut microbiome is often dominated by bacteria from the Bacteroidales, an order that includes Bacteroides and Prevotella In this study, we have identified an acylated amino acid, called glycine lipid, produced by Bacteroides thetaiotaomicron, a beneficial bacterium originally isolated from the human gut. In addition to identifying the genes required for the production of glycine lipids, we show that glycine lipids have an important role during the adaptation of B. thetaiotaomicron to a number of environmental stresses, including exposure to either bile or air. We also show that glycine lipids are important for the normal colonization of the murine gut by B. thetaiotaomicron This work identifies glycine lipids as an important fitness determinant in B. thetaiotaomicron and therefore increases our understanding of the molecular mechanisms underpinning colonization of the mammalian gut by beneficial bacteria.
Asunto(s)
Bacteroides thetaiotaomicron/crecimiento & desarrollo , Aptitud Genética , Glicina/biosíntesis , Lípidos/biosíntesis , Animales , Bacteroides thetaiotaomicron/genética , Femenino , Vida Libre de Gérmenes , Metabolismo de los Lípidos , Ratones , Ratones Endogámicos C57BLRESUMEN
In striated muscle, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have differential effects on the metabolism of glucose and differential effects on the metabolism of protein. We have shown that, despite similar incorporation, treatment of C2C12 myotubes (CM) with EPA but not DHA improves glucose uptake and protein accretion. We hypothesized that these differential effects of EPA and DHA may be due to divergent shifts in lipidomic profiles leading to altered proteomic profiles. We therefore carried out an assessment of the impact of treating CM with EPA and DHA on lipidomic and proteomic profiles. Fatty acid methyl esters (FAME) analysis revealed that both EPA and DHA led to similar but substantials changes in fatty acid profiles with the exception of arachidonic acid, which was decreased only by DHA, and docosapentanoic acid (DPA), which was increased only by EPA treatment. Global lipidomic analysis showed that EPA and DHA induced large alterations in the cellular lipid profiles and in particular, the phospholipid classes. Subsequent targeted analysis confirmed that the most differentially regulated species were phosphatidylcholines and phosphatidylethanolamines containing long-chain fatty acids with five (EPA treatment) or six (DHA treatment) double bonds. As these are typically membrane-associated lipid species we hypothesized that these treatments differentially altered the membrane-associated proteome. Stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics of the membrane fraction revealed significant divergence in the effects of EPA and DHA on the membrane-associated proteome. We conclude that the EPA-specific increase in polyunsaturated long-chain fatty acids in the phospholipid fraction is associated with an altered membrane-associated proteome and these may be critical events in the metabolic remodeling induced by EPA treatment.
Asunto(s)
Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/farmacología , Glucosa/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Proteínas de la Membrana/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Proteoma/efectos de los fármacos , Animales , Metabolismo de los Hidratos de Carbono/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Células Cultivadas , Ácido Eicosapentaenoico/análogos & derivados , Ácidos Grasos/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Músculo Esquelético/metabolismo , Proteoma/metabolismo , Triglicéridos/metabolismoRESUMEN
Glucocerebrosidase (GBA1) gene mutations increase the risk of Parkinson disease (PD). While the cellular mechanisms associating GBA1 mutations and PD are unknown, loss of the glucocerebrosidase enzyme (GCase) activity, inhibition of autophagy and increased α-synuclein levels have been implicated. Here we show that autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase. ALR is a cellular process controlled by mTOR which regenerates functional lysosomes from autolysosomes formed during macroautophagy. A decrease in phopho-S6K levels, a marker of mTOR activity, was observed in models of GCase deficiency, including primary mouse neurons and the PD patient derived fibroblasts with GBA1 mutations, suggesting that ALR is compromised. Importantly Rab7, a GTPase crucial for endosome-lysosome trafficking and ALR, accumulated in GCase deficient cells, supporting the notion that lysosomal recycling is impaired. Recombinant GCase treatment reversed ALR inhibition and lysosomal dysfunction. Moreover, ALR dysfunction was accompanied by impairment of macroautophagy and chaperone-mediated autophagy, increased levels of total and phosphorylated (S129) monomeric α-synuclein, evidence of amyloid oligomers and increased α-synuclein release. Concurrently, we found increased cholesterol and altered glucosylceramide homeostasis which could compromise ALR. We propose that GCase deficiency in PD inhibits lysosomal recycling. Consequently neurons are unable to maintain the pool of mature and functional lysosomes required for the autophagic clearance of α-synuclein, leading to the accumulation and spread of pathogenic α-synuclein species in the brain. Since GCase deficiency and lysosomal dysfunction occur with ageing and sporadic PD pathology, the decrease in lysosomal reformation may be a common feature in PD.
Asunto(s)
Glucosilceramidasa/genética , Neuronas/metabolismo , Enfermedad de Parkinson/genética , alfa-Sinucleína/genética , Proteínas de Unión al GTP rab/genética , Animales , Autofagia/genética , Encéfalo/metabolismo , Encéfalo/patología , Fibroblastos/metabolismo , Fibroblastos/patología , Enfermedad de Gaucher/genética , Enfermedad de Gaucher/patología , Glucosilceramidasa/metabolismo , Humanos , Lisosomas/genética , Lisosomas/metabolismo , Ratones , Mutación , Neuronas/patología , Enfermedad de Parkinson/patología , Proteínas de Unión a GTP rab7RESUMEN
This study was conducted to elucidate patients with early breast cancer preference for standard whole breast irradiation (WBI) or partial breast irradiation (PBI) following lumpectomy, as well as identify important factors for patients when making their treatment decisions. Based on relevant literature and ASTRO consensus statement guidelines, an educational tool and questionnaire were developed. Consenting, eligible women reviewed the educational tool and completed the trade-off questionnaire. Descriptive statistics were calculated, as well as chi-squares and a logistic regression model. Of the 90 patients who completed the study, 62 % preferred WBI, 30 % preferred PBI, 4 % required more information, and 3 % had no preferences. Of the patients who chose WBI, 58 % preferred hypofractionated RT, whereas 25 % preferred the conventional RT regimen. The majority of patients rated recurrence rate [WBI = 55/55 (100 %), PBI = 26/26 (100 %)] and survival [WBI = 54/55 (98 %), PBI = 26/26 (100 %)] as important factors contributing to their choice of treatment preference. Financial factors [WBI = 21/55 (38 %), PBI = 14/26 (53 %)] and convenience [WBI = 36/54 (67 %), PBI = 18/26 (69 %)] were rated as important less frequently. Significantly, more patients who preferred WBI also rated standard method of treatment as important when compared to patients who preferred PBI [WBI = 52/54 (96 %), PBI = 16/26 (61 %), χ 2 = 16.63, p = 0.001]. The majority of patients with early breast cancer who were surveyed for this study preferred WBI as an adjuvant treatment post lumpectomy, yet there was a sizeable minority who preferred PBI. This was associated with the importance patients place on standard treatment. These results will help medical professionals treat patients according to patient values.
Asunto(s)
Neoplasias de la Mama/radioterapia , Mastectomía Segmentaria , Prioridad del Paciente , Adulto , Anciano , Neoplasias de la Mama/cirugía , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Radioterapia Adyuvante/métodosRESUMEN
Stigma and discrimination in relation to mental illnesses have been described as having worse consequences than the conditions themselves. Most medical literature in this area of research has been descriptive and has focused on attitudes towards people with mental illness rather than on interventions to reduce stigma. In this narrative Review, we summarise what is known globally from published systematic reviews and primary data on effective interventions intended to reduce mental-illness-related stigma or discrimination. The main findings emerging from this narrative overview are that: (1) at the population level there is a fairly consistent pattern of short-term benefits for positive attitude change, and some lesser evidence for knowledge improvement; (2) for people with mental illness, some group-level anti-stigma inventions show promise and merit further assessment; (3) for specific target groups, such as students, social-contact-based interventions usually achieve short-term (but less clearly long-term) attitudinal improvements, and less often produce knowledge gains; (4) this is a heterogeneous field of study with few strong study designs with large sample sizes; (5) research from low-income and middle-income countries is conspicuous by its relative absence; (6) caution needs to be exercised in not overgeneralising lessons from one target group to another; (7) there is a clear need for studies with longer-term follow-up to assess whether initial gains are sustained or attenuated, and whether booster doses of the intervention are needed to maintain progress; (8) few studies in any part of the world have focused on either the service user's perspective of stigma and discrimination or on the behaviour domain of behavioural change, either by people with or without mental illness in the complex processes of stigmatisation. We found that social contact is the most effective type of intervention to improve stigma-related knowledge and attitudes in the short term. However, the evidence for longer-term benefit of such social contact to reduce stigma is weak. In view of the magnitude of challenges that result from mental health stigma and discrimination, a concerted effort is needed to fund methodologically strong research that will provide robust evidence to support decisions on investment in interventions to reduce stigma.
Asunto(s)
Trastornos Mentales/psicología , Prejuicio/prevención & control , Estigma Social , Países Desarrollados , Países en Desarrollo , Educación en Salud , Personal de Salud/educación , Humanos , Prejuicio/psicología , Autoimagen , Estudiantes/psicologíaRESUMEN
BACKGROUND: Acute respiratory distress syndrome (ARDS) is an often fatal neutrophil-dominant lung disease. Although influenced by multiple proinflammatory mediators, identification of suitable therapeutic candidates remains elusive. We aimed to delineate the presence of mitochondrial formylated peptides in ARDS and characterise the functional importance of formyl peptide receptor 1 (FPR1) signalling in sterile lung inflammation. METHODS: Mitochondrial formylated peptides were identified in bronchoalveolar lavage fluid (BALF) and serum of patients with ARDS by liquid chromatography-tandem mass spectrometry. In vitro, human neutrophils were stimulated with mitochondrial formylated peptides and their effects assessed by flow cytometry and chemotaxis assay. Mouse lung injury was induced by mitochondrial formylated peptides or hydrochloric acid. Bone marrow chimeras determined the contribution of myeloid and parenchymal FPR1 to sterile lung inflammation. RESULTS: Mitochondrial formylated peptides were elevated in BALF and serum from patients with ARDS. These peptides drove neutrophil activation and chemotaxis through FPR1-dependent mechanisms in vitro and in vivo. In mouse lung injury, inflammation was attenuated in Fpr1-/- mice, effects recapitulated by a pharmacological FPR1 antagonist even when administered after the onset of injury. FPR1 expression was present in alveolar epithelium and chimeric mice demonstrated that both myeloid and parenchymal FPR1 contributed to lung inflammation. CONCLUSIONS: We provide the first definitive evidence of mitochondrial formylated peptides in human disease and demonstrate them to be elevated in ARDS and important in a mouse model of lung injury. This work reveals mitochondrial formylated peptide FPR1 signalling as a key driver of sterile acute lung injury and a potential therapeutic target in ARDS.
Asunto(s)
Receptores de Formil Péptido/inmunología , Síndrome de Dificultad Respiratoria/inmunología , Animales , Líquido del Lavado Bronquioalveolar/química , Quimiotaxis de Leucocito/inmunología , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Citometría de Flujo , Humanos , Ratones , Mitocondrias/inmunología , Activación Neutrófila/inmunología , Neutrófilos/inmunología , Espectrometría de Masas en TándemRESUMEN
We investigated expression of genes mediating elemental cycling at the microspatial scale in the ocean's largest river plume using, to our knowledge, the first fully quantitative inventory of genes and transcripts. The bacterial and archaeal communities associated with a phytoplankton bloom in Amazon River Plume waters at the outer continental shelf in June 2010 harbored â¼ 1.0 × 10(13) genes and 4.7 × 10(11) transcripts per liter that mapped to several thousand microbial genomes. Genomes from free-living cells were more abundant than those from particle-associated cells, and they generated more transcripts per liter for carbon fixation, heterotrophy, nitrogen and phosphorus uptake, and iron acquisition, although they had lower expression ratios (transcripts â gene(-1)) overall. Genomes from particle-associated cells contributed more transcripts for sulfur cycling, aromatic compound degradation, and the synthesis of biologically essential vitamins, with an overall twofold up-regulation of expression compared with free-living cells. Quantitatively, gene regulation differences were more important than genome abundance differences in explaining why microenvironment transcriptomes differed. Taxa contributing genomes to both free-living and particle-associated communities had up to 65% of their expressed genes regulated differently between the two, quantifying the extent of transcriptional plasticity in marine microbes in situ. In response to patchiness in carbon, nutrients, and light at the micrometer scale, Amazon Plume microbes regulated the expression of genes relevant to biogeochemical processes at the ecosystem scale.