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1.
Stem Cell Reports ; 17(9): 2111-2126, 2022 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-36055242

RESUMEN

Disruption of endolysosomal and autophagy-lysosomal systems is increasingly implicated in neurodegeneration. Sodium-proton exchanger 6 (NHE6) contributes to the maintenance of proper endosomal pH, and loss-of function mutations in the X-linked NHE6 lead to Christianson syndrome (CS) in males. Neurodegenerative features of CS are increasingly recognized, with postmortem and clinical data implicating a role for tau. We generated cortical neurons from NHE6 knockout (KO) and isogenic wild-type control human induced pluripotent stem cells. We report elevated phosphorylated and sarkosyl-insoluble tau in NHE6 KO neurons. We demonstrate that NHE6 KO leads to lysosomal and autophagy dysfunction involving reduced lysosomal number and protease activity, diminished autophagic flux, and p62 accumulation. Finally, we show that treatment with trehalose or rapamycin, two enhancers of autophagy-lysosomal function, each partially rescue this tau phenotype. We provide insight into the neurodegenerative processes underlying NHE6 loss of function and into the broader role of the endosome-lysosome-autophagy network in neurodegeneration.


Asunto(s)
Células Madre Pluripotentes Inducidas , Intercambiadores de Sodio-Hidrógeno , Ataxia , Autofagia , Endosomas , Epilepsia , Enfermedades Genéticas Ligadas al Cromosoma X , Humanos , Discapacidad Intelectual , Lisosomas , Masculino , Microcefalia , Neuronas , Trastornos de la Motilidad Ocular , Intercambiadores de Sodio-Hidrógeno/genética
2.
Brain ; 145(9): 3187-3202, 2022 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-34928329

RESUMEN

Loss-of-function mutations in the X-linked endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome in males. Christianson syndrome involves endosome dysfunction leading to early cerebellar degeneration, as well as later-onset cortical and subcortical neurodegeneration, potentially including tau deposition as reported in post-mortem studies. In addition, there is reported evidence of modulation of amyloid-ß levels in experimental models wherein NHE6 expression was targeted. We have recently shown that loss of NHE6 causes defects in endosome maturation and trafficking underlying lysosome deficiency in primary mouse neurons in vitro. For in vivo studies, rat models may have an advantage over mouse models for the study of neurodegeneration, as rat brain can demonstrate robust deposition of endogenously-expressed amyloid-ß and tau in certain pathological states. Mouse models generally do not show the accumulation of insoluble, endogenously-expressed (non-transgenic) tau or amyloid-ß. Therefore, to study neurodegeneration in Christianson syndrome and the possibility of amyloid-ß and tau pathology, we generated an NHE6-null rat model of Christianson syndrome using CRISPR-Cas9 genome-editing. Here, we present the sequence of pathogenic events in neurodegenerating NHE6-null male rat brains across the lifespan. NHE6-null rats demonstrated an early and rapid loss of Purkinje cells in the cerebellum, as well as a more protracted neurodegenerative course in the cerebrum. In both the cerebellum and cerebrum, lysosome deficiency is an early pathogenic event, preceding autophagic dysfunction. Microglial and astrocyte activation also occur early. In the hippocampus and cortex, lysosome defects precede loss of pyramidal cells. Importantly, we subsequently observed biochemical and in situ evidence of both amyloid-ß and tau aggregation in the aged NHE6-null hippocampus and cortex (but not in the cerebellum). Tau deposition is widely distributed, including cortical and subcortical distributions. Interestingly, we observed tau deposition in both neurons and glia, as has been reported in Christianson syndrome post-mortem studies previously. In summary, this experimental model is among very few examples of a genetically modified animal that exhibits neurodegeneration with deposition of endogenously-expressed amyloid-ß and tau. This NHE6-null rat will serve as a new robust model for Christianson syndrome. Furthermore, these studies provide evidence for linkages between endolysosome dysfunction and neurodegeneration involving protein aggregations, including amyloid-ß and tau. Therefore these studies may provide insight into mechanisms of more common neurodegenerative disorders, including Alzheimer's disease and related dementias.


Asunto(s)
Enfermedad de Alzheimer , Microcefalia , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Ataxia , Encéfalo/patología , Modelos Animales de Enfermedad , Epilepsia , Enfermedades Genéticas Ligadas al Cromosoma X , Hipocampo/metabolismo , Discapacidad Intelectual , Lisosomas/metabolismo , Masculino , Microcefalia/genética , Trastornos de la Motilidad Ocular , Ratas , Intercambiadores de Sodio-Hidrógeno/genética , Intercambiadores de Sodio-Hidrógeno/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo
3.
Neuron ; 109(21): 3402-3420.e9, 2021 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-34473944

RESUMEN

We have generated a controlled and manipulable resource that captures genetic risk for Alzheimer's disease: iPSC lines from 53 individuals coupled with RNA and proteomic profiling of both iPSC-derived neurons and brain tissue of the same individuals. Data collected for each person include genome sequencing, longitudinal cognitive scores, and quantitative neuropathology. The utility of this resource is exemplified here by analyses of neurons derived from these lines, revealing significant associations between specific Aß and tau species and the levels of plaque and tangle deposition in the brain and, more importantly, with the trajectory of cognitive decline. Proteins and networks are identified that are associated with AD phenotypes in iPSC neurons, and relevant associations are validated in brain. The data presented establish this iPSC collection as a resource for investigating person-specific processes in the brain that can aid in identifying and validating molecular pathways underlying AD.


Asunto(s)
Enfermedad de Alzheimer , Células Madre Pluripotentes Inducidas , Anciano , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Cognición , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Neuronas/metabolismo , Proteómica , Proteínas tau/genética , Proteínas tau/metabolismo
4.
Front Public Health ; 9: 666715, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33937180

RESUMEN

Previous literature has identified panic buying as often being a response to environmental stressors. In early 2020, we saw an increase in panic buying as a response to a real and/or perceived lack of resources due to COVID-19. Although panic buying has a long history, there is a lack of literature to provide a psychological understanding of the phenomenon. During the early days of COVID-19 clients presented with fear and uncertainty. These negative emotions were, in part, a response to a real shortage of basic supplies. However, the panic response led to behaviors that, for some individuals, resulted in atypical buying patterns. From a therapeutic perspective, one can consider behavioral and psychodynamic explanations and interventions, and how this impacts the associated behaviors. This article will focus on psychodynamic understandings of panic buying as a response to events that result in negative emotions. By providing a psychodynamic understanding of panic buying, authors hope to contribute to the therapy of clients presenting with related behaviors and their associated negative affect.


Asunto(s)
COVID-19 , Trastorno de Pánico , Comportamiento del Consumidor , Humanos , Pánico , Trastorno de Pánico/terapia , SARS-CoV-2
5.
J Fr Ophtalmol ; 44(6): 828-834, 2021 Jun.
Artículo en Francés | MEDLINE | ID: mdl-33846032

RESUMEN

In adults, the management of keratoconus has evolved in recent years to achieve a well-codified treatment algorithm. The technique of cross-linking (CXL) has allowed us to stabilize the progression of keratoconus and has been largely developed. It is very effective, with few postoperative complications. Currently, there is no specific keratoconus management protocol for children. As we already know that keratoconus usually evolves more rapidly in children, we might consider whether a stabilizing treatment should be proposed as first-line therapy at the time of diagnosis. We carried out a retrospective study including patients less than 18 years of age with keratoconus who consulted the ophthalmology department at Edouard Herriot hospital in Lyon between 2013 and 2017. The main study parameter was whether or not CXL was performed. The other parameters were gender, age, ethnicity, eye rubbing, presence or absence of atopic disease, maximum keratometry (Kmax), minimal pachymetry, best corrected visual acuity (BCVA) and spherical equivalent. Forty-eight eyes of 34 patients were included. We found that two-thirds of the patients were Caucasian boys. Half of the patients had allergies, and over 60% of patients rubbed their eyes regularly. Only six percent of patients had a family history of keratoconus. The mean age of the patients was 14 (7-18) years at the time of diagnosis. Thirty-four eyes of 22 patients underwent CXL, for a total of 71% of our cohort. No postoperative complications occurred. After CXL, there was no significant difference in minimum pachymetry (455.6±37.25µm vs. 453.45±42.6µm after treatment (P=0.71)) or Kmax (50.23±7.17D vs. 50.99±7.01D after treatment (P=0.058)). There was a significant improvement in BCVA (from 0.30±0.3LogMar to 0.17±0.17LogMar after CXL (P=0.024)) and spherical equivalent (-1.91±2.1D to -2.54±1.89D after treatment (P=0.009)). The mean duration of follow-up was 32.2 months (12-59). CXL shows long-term disease stabilization in children with keratoconus. Nevertheless, this technique is indicated only for progressive keratoconus. Early diagnosis and management are essential in this population where the disease is rapidly changing. Treatment of atopy and performance of corneal topography when a child has irregular astigmatism should become automatic for early detection of this disease.


Asunto(s)
Queratocono , Fotoquimioterapia , Adolescente , Adulto , Niño , Colágeno/uso terapéutico , Topografía de la Córnea , Reactivos de Enlaces Cruzados/uso terapéutico , Epitelio , Estudios de Seguimiento , Humanos , Queratocono/tratamiento farmacológico , Masculino , Fármacos Fotosensibilizantes/uso terapéutico , Estudios Retrospectivos , Riboflavina/uso terapéutico , Rayos Ultravioleta , Agudeza Visual
6.
Exp Mech ; 61(1): 41-51, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33746235

RESUMEN

BACKGROUND: Elastic fibers are composed primarily of the protein elastin and they provide reversible elasticity to the large arteries. Degradation of elastic fibers is a common histopathology in aortic aneurysms. Pentagalloyl glucose (PGG) has been shown to bind elastin and stabilize elastic fibers in some in vitro studies and in vivo models of abdominal aortic aneurysms, however its effects on native arteries are not well described. OBJECTIVE: Perform detailed studies of the biomechanical effects of PGG on native arteries and the preventative capabilities of PGG for elastin degraded arteries. METHODS: We treated mouse carotid arteries with PGG, elastase (ELA), and PGG+ELA and compared the wall structure, solid mechanics, and fluid transport properties to untreated (UNT) arteries. RESULTS: We found that PGG alone decreased compliance compared to UNT arteries, but did not affect any other structural or biomechanical measures. Mild (30 sec) ELA treatment caused collapse and fragmentation of the elastic lamellae, plastic deformation, decreased compliance, increased modulus, and increased hydraulic conductance of the arterial wall compared to UNT. PGG+ELA treatment partially protected from all of these changes, in particular the plastic deformation. PGG mechanical protection varied considerably across PGG+ELA samples and appeared to correlate with the structural changes. CONCLUSIONS: Our results provide important considerations for the effects of PGG on native arteries and a baseline for further biomechanical studies on preventative elastic fiber stabilization.

7.
Phys Rev Lett ; 126(2): 027201, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33512209

RESUMEN

The spin absorption process in a ferromagnetic material depends on the spin orientation relative to the magnetization. Using a ferromagnet to absorb the pure spin current created within a lateral spin valve, we evidence and quantify a sizable orientation dependence of the spin absorption in Co, CoFe, and NiFe. These experiments allow us to determine the spin-mixing conductance, an elusive but fundamental parameter of the spin-dependent transport. We show that the obtained values cannot be understood within a model considering only the Larmor, transverse decoherence, and spin diffusion lengths, and rather suggest that the spin-mixing conductance is actually limited by the Sharvin conductance.

8.
BMC Health Serv Res ; 21(1): 100, 2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33514362

RESUMEN

BACKGROUND: The Improving Wisely intervention is a peer-to-peer audit and feedback intervention to reduce overuse of Mohs Micrographic Surgery (MMS). The objective of this study was to conduct a process evaluation to evaluate Mohs surgeons' perceptions of the implementation quality and perceived impact of the Improving Wisely intervention. METHODS: Surgeons in the Improving Wisely intervention arm, comprised of members of the American College of Mohs Surgeons (ACMS) who co-led the intervention, were invited to complete surveys and key informant interviews. Participants described perceptions of implementation quality (evaluated via dose, quality of implementation, reach and participant responsiveness), perceived impact of the Improving Wisely intervention (evaluated on a 1-5 Likert and qualitatively), and barriers and facilitators to changing surgeons' clinical practice patterns to reduce Mohs overuse. RESULTS: Seven hundred thirty-seven surgeons participated in the survey. 89% were supportive of the intervention. Participants agreed that the intervention would improve patient care and reduce the annual costs of Mohs surgery. Thirty surgeons participated in key informant interviews. 93% were interested in receiving additional data reports in the future. Participants recommended the reports be disseminated annually, that the reports be expanded to include appropriateness data, and that the intervention be extended to non ACMS members. Six themes identifying factors impacting potential MMS overuse were identified. CONCLUSIONS: Participants were strongly supportive of the intervention. We present the template used to design and implement the Improving Wisely intervention and provide suggestions for specialty societies interested in leading similar quality improvement interventions among their members.


Asunto(s)
Neoplasias Cutáneas , Cirujanos , Humanos , Cirugía de Mohs , Pautas de la Práctica en Medicina , Encuestas y Cuestionarios
9.
J Evol Biol ; 34(2): 364-379, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33190382

RESUMEN

Congeneric parasites are unlikely to specialize on the same tissues of the same host species, likely because of strong multifarious selection against niche overlap. Exceptions where >1 congeneric species use the same tissues reveal important insights into ecological factors underlying the origins and maintenance of diversity. Larvae of sunflower maggot flies in the genus Strauzia feed on plants in the family Asteraceae. Although Strauzia tend to be host specialists, some species specialize on the same hosts. To resolve the origins of host sharing among these specialist flies, we used reduced representation genomic sequencing to infer the first multilocus phylogeny of genus Strauzia. Our results show that Helianthus tuberosus and Helianthus grosseserratus each host three different Strauzia species and that the flies co-occurring on a host are not one another's closest relatives. Though this pattern implies that host sharing is most likely the result of host shifts, these may not all be host shifts in the conventional sense of an insect moving onto an entirely new plant. Many hosts of Strauzia belong to a clade of perennial sunflowers that arose 1-2 MYA and are noted for frequent introgression and hybrid speciation events. Our divergence time estimates for all of the Helianthus-associated Strauzia are within this same time window (<1 MYA), suggesting that rapid and recent adaptive introgression and speciation in Helianthus may have instigated the diversification of Strauzia, with some flies converging upon a single plant host after their respective ancestral host plants hybridized to form a new sunflower species.


Asunto(s)
Especiación Genética , Helianthus , Herbivoria , Filogenia , Tephritidae/genética , Animales , Larva/fisiología
10.
Nature ; 580(7802): 216-219, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32269349

RESUMEN

Present estimates suggest that of the 359 million tons of plastics produced annually worldwide1, 150-200 million tons accumulate in landfill or in the natural environment2. Poly(ethylene terephthalate) (PET) is the most abundant polyester plastic, with almost 70 million tons manufactured annually worldwide for use in textiles and packaging3. The main recycling process for PET, via thermomechanical means, results in a loss of mechanical properties4. Consequently, de novo synthesis is preferred and PET waste continues to accumulate. With a high ratio of aromatic terephthalate units-which reduce chain mobility-PET is a polyester that is extremely difficult to hydrolyse5. Several PET hydrolase enzymes have been reported, but show limited productivity6,7. Here we describe an improved PET hydrolase that ultimately achieves, over 10 hours, a minimum of 90 per cent PET depolymerization into monomers, with a productivity of 16.7 grams of terephthalate per litre per hour (200 grams per kilogram of PET suspension, with an enzyme concentration of 3 milligrams per gram of PET). This highly efficient, optimized enzyme outperforms all PET hydrolases reported so far, including an enzyme8,9 from the bacterium Ideonella sakaiensis strain 201-F6 (even assisted by a secondary enzyme10) and related improved variants11-14 that have attracted recent interest. We also show that biologically recycled PET exhibiting the same properties as petrochemical PET can be produced from enzymatically depolymerized PET waste, before being processed into bottles, thereby contributing towards the concept of a circular PET economy.


Asunto(s)
Hidrolasas/química , Hidrolasas/metabolismo , Plásticos/química , Plásticos/metabolismo , Tereftalatos Polietilenos/química , Tereftalatos Polietilenos/metabolismo , Ingeniería de Proteínas , Reciclaje , Actinobacteria/enzimología , Burkholderiales/enzimología , Hidrolasas de Éster Carboxílico/química , Hidrolasas de Éster Carboxílico/metabolismo , Disulfuros/química , Disulfuros/metabolismo , Pruebas de Enzimas , Estabilidad de Enzimas , Fusarium/enzimología , Modelos Moleculares , Ácidos Ftálicos/metabolismo , Polimerizacion , Thermobifida
11.
Phys Rev Lett ; 124(2): 027201, 2020 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-32004027

RESUMEN

Relating magnetotransport properties to specific spin textures at surfaces or interfaces is an intense field of research nowadays. Here, we investigate the variation of the electrical resistance of Ge(111) grown epitaxially on semi-insulating Si(111) under the application of an external magnetic field. We find a magnetoresistance term that is linear in current density j and magnetic field B, hence, odd in j and B, corresponding to a unidirectional magnetoresistance. At 15 K, for I=10 µA (or j=0.33 A m^{-1}) and B=1 T, it represents 0.5% of the zero field resistance, a much higher value compared to previous reports on unidirectional magnetoresistance (UMR). We ascribe the origin of this magnetoresistance to the interplay between the externally applied magnetic field and the pseudomagnetic field generated by the current applied in the spin-splitted subsurface states of Ge(111). This unidirectional magnetoresistance is independent of the current direction with respect to the Ge crystal axes. It progressively vanishes, either using a negative gate voltage due to carrier activation into the bulk (without spin-splitted bands), or by increasing the temperature due to the Rashba energy splitting of the subsurface states lower than ∼58k_{B}. We believe that UMR could be used as a powerful probe of the spin-orbit interaction in a wide range of materials.

12.
Nat Commun ; 10(1): 2076, 2019 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-31061386

RESUMEN

Production of 1-butene, a major monomer in polymer industry, is dominated by homogeneous protocols via ethylene dimerization. Homogeneous catalysts can achieve high selectivity but require large amounts of activators and solvents, and exhibit poor recyclability; in turn, heterogeneous systems are robust but lack selectivity. Here we show how the precise engineering of metal-organic frameworks (MOFs) holds promise for a sustainable process. The key to the (Ru)HKUST-1 MOF activity is the intrapore reactant condensation that enhances ethylene dimerization with high selectivity (> 99% 1-butene) and high stability (> 120 h) in the absence of activators and solvents. According to spectroscopy, kinetics, and modeling, the engineering of defective nodes via controlled thermal approaches rules the activity, while intrapore ethylene condensation accounts for selectivity and stability. The combination of well-defined actives sites with the concentration effect arising from condensation regimes paves the way toward the development of robust MOF catalysts for diverse gas-phase reactions.

14.
Anaesthesist ; 67(6): 452-457, 2018 06.
Artículo en Alemán | MEDLINE | ID: mdl-29500580

RESUMEN

Entrustable professional activities (EPAs) are characterized as self-contained units of work in a given typical clinical context, which may be entrusted to a trainee for independent execution at a certain point of training. An example could be the intraoperative anesthesia management of an ASA 1 patient for an uncomplicated surgical intervention as an EPA in early postgraduate anesthesia training. The EPAs can be described as an evolution of a competency-based medical educational concept, applying the concept of the competencies of a person to specific workplace contexts. In this way the expected level of skills and supervision at a certain stage of training have a more practical meaning and the danger of fragmentation of individual competencies in the competence-based model is avoided. It is a more holistic view of a trainee. Experience with this new concept is so far limited, therefore, further studies are urgently needed to determine whether and how EPAs can contribute to improvements in further training.


Asunto(s)
Anestesiología/educación , Educación Médica Continua/tendencias , Competencia Clínica , Educación Basada en Competencias , Curriculum , Humanos , Internado y Residencia
15.
BMC Evol Biol ; 18(1): 30, 2018 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-29540154

RESUMEN

BACKGROUND: Much evolutionary theory predicts that diversity arises via both adaptive radiation (diversification driven by selection against niche-overlap within communities) and divergence of geographically isolated populations. We focus on tropical fruit flies (Blepharoneura, Tephritidae) that reveal unexpected patterns of niche-overlap within local communities. Throughout the Neotropics, multiple sympatric non-interbreeding populations often share the same highly specialized patterns of host use (e.g., flies are specialists on flowers of a single gender of a single species of host plants). Lineage through time (LTT) plots can help distinguish patterns of diversification consistent with ecologically limited adaptive radiation from those predicted by ecologically neutral theories. Here, we use a time-calibrated phylogeny of Blepharoneura to test the hypothesis that patterns of Blepharoneura diversification are consistent with an "ecologically neutral" model of diversification that predicts that diversification is primarily a function of time and space. RESULTS: The Blepharoneura phylogeny showed more cladogenic divergence associated with geography than with shifts in host-use. Shifts in host-use were associated with ~ 20% of recent splits (< 3 Ma), but > 60% of older splits (> 3 Ma). In the overall tree, gamma statistic and maximum likelihood model fitting showed no evidence of diversification rate changes though there was a weak signature of slowing diversification rate in one of the component clades. CONCLUSIONS: Overall patterns of Blepharoneura diversity are inconsistent with a traditional explanation of adaptive radiation involving decreases in diversification rates associated with niche-overlap. Sister lineages usually use the same host-species and host-parts, and multiple non-interbreeding sympatric populations regularly co-occur on the same hosts. We suggest that most lineage origins (phylogenetic splits) occur in allopatry, usually without shifts in host-use, and that subsequent dispersal results in assembly of communities composed of multiple sympatric non-interbreeding populations of flies that share the same hosts.


Asunto(s)
Tephritidae/clasificación , Tephritidae/genética , Animales , Biodiversidad , Evolución Biológica , Ecología , Flores , Especiación Genética , Geografía , Herbivoria , Funciones de Verosimilitud , Filogenia , Plantas , Simpatría
16.
J Hosp Infect ; 99(2): 192-199, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29432818

RESUMEN

OBJECTIVES: Differential time to positivity of cultures of blood drawn simultaneously from central venous catheter and peripheral sites is widely used to diagnose catheter-related bloodstream infections without removing the catheter. However, the accuracy of this technique for some pathogens, such as Staphylococcus aureus, is debated in routine practice. METHODS: In a 320-bed reference cancer centre, the charts of patients with at least one blood culture positive for S. aureus among paired blood cultures drawn over a six-year period were studied retrospectively. Microbiological data were extracted from the prospectively compiled database of the microbiology unit. Data concerning the 149 patients included were reviewed retrospectively by independent physicians blinded to the absolute and differential times to positivity, in order to establish or refute the diagnosis of catheter-related sepsis. Due to missing data, 48 charts were excluded, so 101 cases were actually analysed. The diagnosis was established in 62 cases, refuted in 15 cases and inconclusive in the remaining 24 cases. RESULTS: For the 64 patients with both central and peripheral positive blood cultures, the differential positivity time was significantly greater for patients with catheter-related bloodstream infections due to S. aureus (P<0.02). However, because of the high number of false-negative cases, the classic cut-off limit of 120 min showed 100% specificity but only 42% sensitivity for the diagnosis of catheter-related bloodstream infection due to S. aureus. CONCLUSIONS: These results strongly suggest that despite its high specificity, the differential time to positivity may not be reliable to rule out catheter-related bloodstream infection due to S. aureus.


Asunto(s)
Cultivo de Sangre/métodos , Infecciones Relacionadas con Catéteres/diagnóstico , Sepsis/diagnóstico , Infecciones Estafilocócicas/diagnóstico , Staphylococcus aureus/aislamiento & purificación , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y Especificidad , Factores de Tiempo
17.
Stem Cell Reports ; 9(6): 1868-1884, 2017 12 12.
Artículo en Inglés | MEDLINE | ID: mdl-29153990

RESUMEN

Alzheimer's disease (AD) induces memory and cognitive impairment in the absence of motor and sensory deficits during its early and middle course. A major unresolved question is the basis for this selective neuronal vulnerability. Aß, which plays a central role in AD pathogenesis, is generated throughout the brain, yet some regions outside of the limbic and cerebral cortices are relatively spared from Aß plaque deposition and synapse loss. Here, we examine neurons derived from iPSCs of patients harboring an amyloid precursor protein mutation to quantify AD-relevant phenotypes following directed differentiation to rostral fates of the brain (vulnerable) and caudal fates (relatively spared) in AD. We find that both the generation of Aß and the responsiveness of TAU to Aß are affected by neuronal cell type, with rostral neurons being more sensitive than caudal neurons. Thus, cell-autonomous factors may in part dictate the pattern of selective regional vulnerability in human neurons in AD.


Asunto(s)
Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/genética , Células Madre Pluripotentes Inducidas/metabolismo , Neuronas/metabolismo , Proteínas tau/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Diferenciación Celular/genética , Linaje de la Célula/genética , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Regulación del Desarrollo de la Expresión Génica/genética , Humanos , Células Madre Pluripotentes Inducidas/patología , Ratones , Neuronas/patología , Fenotipo , Proteínas tau/metabolismo
18.
Br J Anaesth ; 119(5): 1009-1014, 2017 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-28981584

RESUMEN

Background: Postgraduate specialty training has traditionally been based on a time- and rotation-based model, but competency-based models are emerging. Because anaesthesia training evolves differently across Europe, variations in assessment and certification processes are expected, but the extent of similarities and differences is unknown. The aim of this study was to compare anaesthesia training programmes in Europe, focusing on assessment and certification processes. Methods: We performed an online survey among national representatives of the Union of European Medical Specialists/European Board of Anaesthesiology. Results: All 36 countries participated. Duration of training had a median of 5 yr (range 2.75-7). Mean number of different assessment tools was 7.45 (range 4-13), with more tools being used in competency-based programmes [mean 9.1 (sd 2.97) vs 7.0 (sd 1.97); P=0.03]. Most countries had a nationally uniform certification process. Based on a qualitative analysis of the survey findings, a categorization of countries emerged, reflecting the approach to assessment and certification. We observed two main streams of countries with an underlying knowledge or procedural focus within a time- and rotation-based apprenticeship model. These main streams are evolving, to different extents, towards a third orientation, competency-based training. Conclusions: Assessment and certification processes in European anaesthesia training are diverse. In many countries, a time-based apprenticeship model is evolving towards a competency-based certification process. This diversity precludes comparison of competence of graduating anaesthetists across Europe.


Asunto(s)
Anestesiología/educación , Certificación/métodos , Educación de Postgrado en Medicina/métodos , Evaluación Educacional/métodos , Educación Médica Continua/métodos , Europa (Continente) , Humanos , Especialización
19.
J Biol Chem ; 292(48): 19873-19889, 2017 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-29021256

RESUMEN

Amyloid plaques, a neuropathological hallmark of Alzheimer's disease, are largely composed of amyloid ß (Aß) peptide, derived from cleavage of amyloid precursor protein (APP) by ß- and γ-secretases. The endosome is increasingly recognized as an important crossroad for APP and these secretases, with major implications for APP processing and amyloidogenesis. Among various post-translational modifications affecting APP accumulation, ubiquitination of cytodomain lysines may represent a key signal controlling APP endosomal sorting. Here, we show that substitution of APP C-terminal lysines with arginine disrupts APP ubiquitination and that an increase in the number of substituted lysines tends to increase APP metabolism. An APP mutant lacking all C-terminal lysines underwent the most pronounced increase in processing, leading to accumulation of both secreted and intracellular Aß40. Artificial APP ubiquitination with rapalog-mediated proximity inducers reduced Aß40 generation. A lack of APP C-terminal lysines caused APP redistribution from endosomal intraluminal vesicles (ILVs) to the endosomal limiting membrane, with a subsequent decrease in APP C-terminal fragment (CTF) content in secreted exosomes, but had minimal effects on APP lysosomal degradation. Both the increases in secreted and intracellular Aß40 were abolished by depletion of presenilin 2 (PSEN2), recently shown to be enriched on the endosomal limiting membrane compared with PSEN1. Our findings demonstrate that ubiquitin can act as a signal at five cytodomain-located lysines for endosomal sorting of APP. They further suggest that disruption of APP endosomal sorting reduces its sequestration in ILVs and results in PSEN2-mediated processing of a larger pool of APP-CTF on the endosomal membrane.


Asunto(s)
Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Fragmentos de Péptidos/metabolismo , Presenilina-2/metabolismo , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/genética , Arginina/genética , Línea Celular , Endosomas/metabolismo , Humanos , Lisina/genética , Mutación , Proteolisis , Ubiquitinación
20.
J Fr Ophtalmol ; 40(7): 592-605, 2017 Sep.
Artículo en Francés | MEDLINE | ID: mdl-28802684

RESUMEN

PURPOSE: To evaluate the long-term outcomes of artificial iris intraocular lenses sutured to the sclera for managing traumatic aphakia and aniridia. METHODS: All consecutive cases receiving a Morcher® combination implant from June 2008 to February 2016 in Edouard-Herriot Hospital (Lyon, France) were included in this single-center retrospective study. Visual acuity, subjective degree of glare, quality of life and surgical complications were evaluated. RESULTS: Seventeen eyes of 17 patients were included, among which 82% were male. The mean age was 42 years. The injuries consisted of 23.5% contusion and 70.5% open globe injuries, of which 41% were globe ruptures. There was one postoperative case. A penetrating keratoplasty was performed at the same time for eight eyes. The mean follow-up was 32 months. Best-corrected visual acuity improved in 41.2%, remained the same in 17.6% and decreased in 41.2% of our cases. Distance vision averaged 1±0.25 line better and near vision 2.2±0.32 lines better when visual acuity was quantifiable before surgery. Glare improved in 80% of patients and remained stable in 20%, decreasing on average from 3.3/5 [min. 3-max. 4; SD: 0.48] before surgery to 1.9/5 [min. 0-max. 4; SD: 1.197] after surgery. Regarding the esthetic results, 78% of the patients declared themselves reasonably to very satisfied; 57% reported no limitation of activities of daily living, and 43% reported mild limitation. Ocular hypertension and glaucoma, found in 40% of eyes, were the main postoperative complications. CONCLUSION: Implantation of prosthetic iris device combined with an intraocular lens appears to be safe and effective in reducing glare disability and improving visual acuity. Close, long-term monitoring is essential for the success of this surgery.


Asunto(s)
Aniridia/cirugía , Afaquia/cirugía , Lesiones Oculares/cirugía , Ojo Artificial , Iris/cirugía , Implantación de Lentes Intraoculares/métodos , Esclerótica/cirugía , Adulto , Anciano , Aniridia/etiología , Afaquia/etiología , Lesiones Oculares/complicaciones , Femenino , Humanos , Iris/patología , Implantación de Lentes Intraoculares/efectos adversos , Lentes Intraoculares/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Esclerótica/patología , Técnicas de Sutura/efectos adversos , Suturas/efectos adversos , Adulto Joven
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