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We assembled genome-wide data from 16 prehistoric Africans. We show that the anciently divergent lineage that comprises the primary ancestry of the southern African San had a wider distribution in the past, contributing approximately two-thirds of the ancestry of Malawi hunter-gatherers â¼8,100-2,500 years ago and approximately one-third of the ancestry of Tanzanian hunter-gatherers â¼1,400 years ago. We document how the spread of farmers from western Africa involved complete replacement of local hunter-gatherers in some regions, and we track the spread of herders by showing that the population of a â¼3,100-year-old pastoralist from Tanzania contributed ancestry to people from northeastern to southern Africa, including a â¼1,200-year-old southern African pastoralist. The deepest diversifications of African lineages were complex, involving either repeated gene flow among geographically disparate groups or a lineage more deeply diverging than that of the San contributing more to some western African populations than to others. We finally leverage ancient genomes to document episodes of natural selection in southern African populations. PAPERCLIP.
Assuntos
População Negra/genética , Genoma Humano , África , Osso e Ossos/química , DNA Antigo/análise , Feminino , Fósseis , Genética Médica , Genética Populacional , Estudo de Associação Genômica Ampla , Humanos , Estilo de Vida , MasculinoRESUMO
Multiple lines of genetic and archaeological evidence suggest that there were major demographic changes in the terminal Late Pleistocene epoch and early Holocene epoch of sub-Saharan Africa1-4. Inferences about this period are challenging to make because demographic shifts in the past 5,000 years have obscured the structures of more ancient populations3,5. Here we present genome-wide ancient DNA data for six individuals from eastern and south-central Africa spanning the past approximately 18,000 years (doubling the time depth of sub-Saharan African ancient DNA), increase the data quality for 15 previously published ancient individuals and analyse these alongside data from 13 other published ancient individuals. The ancestry of the individuals in our study area can be modelled as a geographically structured mixture of three highly divergent source populations, probably reflecting Pleistocene interactions around 80-20 thousand years ago, including deeply diverged eastern and southern African lineages, plus a previously unappreciated ubiquitous distribution of ancestry that occurs in highest proportion today in central African rainforest hunter-gatherers. Once established, this structure remained highly stable, with limited long-range gene flow. These results provide a new line of genetic evidence in support of hypotheses that have emerged from archaeological analyses but remain contested, suggesting increasing regionalization at the end of the Pleistocene epoch.
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População Negra , DNA Antigo , Genética Populacional , África Subsaariana , Arqueologia , População Negra/genética , População Negra/história , DNA Antigo/análise , Fluxo Gênico/genética , Genoma Humano/genética , História Antiga , HumanosRESUMO
Population history-focused DNA and ancient DNA (aDNA) research in Africa has dramatically increased in the past decade, enabling increasingly fine-scale investigations into the continent's past. However, while international interest in human genomics research in Africa grows, major structural barriers limit the ability of African scholars to lead and engage in such research and impede local communities from partnering with researchers and benefitting from research outcomes. Because conversations about research on African people and their past are often held outside Africa and exclude African voices, an important step for African DNA and aDNA research is moving these conversations to the continent. In May 2023 we held the DNAirobi workshop in Nairobi, Kenya and here we synthesize what emerged most prominently in our discussions. We propose an ideal vision for population history-focused DNA and aDNA research in Africa in ten years' time and acknowledge that to realize this future, we need to chart a path connecting a series of "landmarks" that represent points of consensus in our discussions. These include effective communication across multiple audiences, reframed relationships and capacity building, and action toward structural changes that support science and beyond. We concluded there is no single path to creating an equitable and self-sustaining research ecosystem, but rather many possible routes linking these landmarks. Here we share our diverse perspectives as geneticists, anthropologists, archaeologists, museum curators, and educators to articulate challenges and opportunities for African DNA and aDNA research and share an initial map toward a more inclusive and equitable future.
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DNA Antigo , Genética Populacional , Humanos , DNA Antigo/análise , África , Genômica , População Negra/genéticaRESUMO
Recent genomic data have revealed multiple interactions between Neanderthals and modern humans, but there is currently little genetic evidence regarding Neanderthal behaviour, diet, or disease. Here we describe the shotgun-sequencing of ancient DNA from five specimens of Neanderthal calcified dental plaque (calculus) and the characterization of regional differences in Neanderthal ecology. At Spy cave, Belgium, Neanderthal diet was heavily meat based and included woolly rhinoceros and wild sheep (mouflon), characteristic of a steppe environment. In contrast, no meat was detected in the diet of Neanderthals from El Sidrón cave, Spain, and dietary components of mushrooms, pine nuts, and moss reflected forest gathering. Differences in diet were also linked to an overall shift in the oral bacterial community (microbiota) and suggested that meat consumption contributed to substantial variation within Neanderthal microbiota. Evidence for self-medication was detected in an El Sidrón Neanderthal with a dental abscess and a chronic gastrointestinal pathogen (Enterocytozoon bieneusi). Metagenomic data from this individual also contained a nearly complete genome of the archaeal commensal Methanobrevibacter oralis (10.2× depth of coverage)-the oldest draft microbial genome generated to date, at around 48,000 years old. DNA preserved within dental calculus represents a notable source of information about the behaviour and health of ancient hominin specimens, as well as a unique system that is useful for the study of long-term microbial evolution.
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DNA Antigo/análise , Cálculos Dentários/química , Dieta/história , Preferências Alimentares , Saúde/história , Homem de Neandertal/microbiologia , Homem de Neandertal/psicologia , Animais , Bélgica , Carnivoridade , Cavernas , Enterocytozoon/genética , Enterocytozoon/isolamento & purificação , Genoma Bacteriano/genética , História Antiga , Humanos , Intestinos/microbiologia , Carne/história , Methanobrevibacter/genética , Methanobrevibacter/isolamento & purificação , Boca/microbiologia , Pan troglodytes/microbiologia , Penicillium/química , Perissodáctilos , Ovinos , Espanha , Estômago/microbiologia , Simbiose , Fatores de Tempo , Vegetarianos/históriaRESUMO
Empirical research on international student migrants has sometimes homogenised this group, framing it as predominantly made up of privileged members of the global middle-class. This has led to calls to acknowledge and address the precarity faced by international students in their respective host countries more comprehensively. This study aims to explore how levels of financial precarity vary among international students in Australia, and how this in turn contributes to varying levels of precariousness in the personal spheres of students' lives. In doing so, we centre and refine the concept of precarity for use in studies of internationally mobile students, arguing for its use as a 'relational nexus', bridging financial precarity and broader lived experiences. Drawing on a large-scale survey and semi-structured interviews with 48 students, we emphasise the linkages between financial precarity and precariousness as a socio-ontological experience, explored through the examples of time poverty, physical and mental wellbeing, and relationships.
RESUMO
Housing is a major concern for many international students. This is especially so in those countries where students are mostly dependent on the private market for their accommodation. Australia is one such country, and is one of the world's major destinations for international students. This article analyses governmental failure to address problems relating to international student housing affordability and conditions. Using theory on 'policy inaction' to frame the analysis, we draw on 20 interviews with policy stakeholders to explain the Australian government's reliance on: (1) market-based housing provision for international students, and (2) a longstanding policy preference not to provide support. Interviewees were widely critical of the lack of action to address international student housing problems and understood inaction in relation, rather than in opposition, to the dominance of market-based action in housing and higher education. However, analysis of stakeholder perspectives also illuminates how policy-making action benefiting some emerges as inaction for others left behind or overlooked by the status quo. The interview data points to the need for government to overhaul its policy framework, and in doing so, to collaborate with higher education providers in revising the market-based regulatory approach. The main implications for theory and policy are discussed.
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INTRODUCTION: Endurance athletes are at higher risk for developing atrial fibrillation as compared to the general population. The exact mechanism to explain this observation is incompletely understood. Our study aimed to determine whether degree of left atrial fibrosis detected by late gadolinium-enhancement magnetic resonance imaging (LGE-MRI) differed between Masters athletes and non-athlete controls. METHODS: We recruited 20 endurance healthy Masters athletes and 20 healthy control subjects who underwent cardiac MRI. Healthy controls were recruited during screening colonoscopies and Masters athletes were recruited through word of mouth and at competitions. The two groups were age and gender matched. None of the participants were known to have an arrhythmia. Fibrosis, as measured by late gadolinium-enhancement, was measured in each participant by blinded readers. The degree of left atrial fibrosis was compared between the two groups. All participants were recruited from the Salt Lake City region and scanned at the University of Utah healthcare complex. RESULTS: Left ventricular function was normal in all study participants. Left atrial volumes were significantly larger in the athletes (74.2 ml⯱â¯14.4) as compared to the healthy control subjects (60.8â¯mL⯱â¯21.4) (Pâ¯=â¯.02). Mean left atrial fibrosis score, reported as a percentage of the LA, was 15.5%⯱â¯5.9 in the athlete cohort compared to 9.6%⯱â¯4.9 in the controls (Pâ¯=â¯.002). CONCLUSIONS: To our knowledge this is the first study that describes, characterizes and specifically quantifies fibrotic changes within the left atrium of highly trained endurance athletes. Increased atrial fibrosis seen in this population may be an early indicator for endurance athletes at risk of developing atrial arrhythmias.
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Treino Aeróbico/efeitos adversos , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/patologia , Imageamento por Ressonância Magnética , Adulto , Estudos de Coortes , Meios de Contraste , Treino Aeróbico/métodos , Feminino , Fibrose/diagnóstico por imagem , Fibrose/etiologia , Gadolínio , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , EsportesRESUMO
BACKGROUND: Cryoballoon ablation (CBA) for pulmonary vein isolation (PVI) is an established modality for the treatment of atrial fibrillation (AF). We report feasibility of left atrial (LA) substrate modification in addition to PVI both using the cryoballoon. METHODS: LA substrates and CBA-induced scar were assessed at baseline and 3 months after ablation using late gadolinium enhancement magnetic resonance imaging (LGE-MRI). Common periprocedural data including postablation LGE-MRI for evaluation of esophageal thermal injury, and CBA-associated complications were collected. Freedom from AF recurrence at 12 months was assessed using Holter and 30-day rhythm monitors. RESULTS: In 26 patients (64 ± 11 years, 69% male; 27% persistent AF, CHADSVASC score: 2.3 ± 1.5; left ventricular ejection fraction: 56 ± 10%, oral anticoagulation with warfarin/direct oral anticoagulants: n = 11/15), referred for first-time AF ablation, CBA of the pulmonary veins and extrapulmonary LA substrates was performed (median: 12 [interquartile range {IQR}: 7-14] freezes over 1675 seconds [IQR: 1168-2160]). On LGE-MRI, significant postablation cryoballoon-induced LA scar (median: 19.4% [IQR: 13.4-24.7] in comparison to baseline preablation LA-LGE (median: 10.6% [IQR 3.1-13.1]; P = .01) was found. Freedom from AF recurrence at 12 months was 74.5% with median time-to-recurrence of 242 days (IQR: 172-298). In 15 of 26 (58%) patients, esophageal enhancement on the postablation MRI was present with full recovery after 3 months. No major periprocedural complications were observed. CONCLUSION: LA substrate modification in addition to PVI using LGE-MRI-guided CBA is feasible but still experimental. The efficacy and safety have to be investigated in a prospective randomized trial.
Assuntos
Fibrilação Atrial , Ablação por Cateter , Imageamento por Ressonância Magnética , Veias Pulmonares , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Meios de Contraste , Feminino , Gadolínio , Átrios do Coração/cirurgia , Humanos , Masculino , Estudos Prospectivos , Veias Pulmonares/diagnóstico por imagem , Veias Pulmonares/cirurgia , Recidiva , Resultado do TratamentoRESUMO
BACKGROUND: Left atrial (LA) fibrosis is thought to be a substrate for atrial fibrillation (AF) and can be quantified by late gadolinium enhancement magnetic resonance imaging (LGE-MRI). Fibrosis formation in LA is a dynamic process and may either progress or regress following AF ablation. We examined the impact of postablation progression in LA fibrosis on AF recurrence. METHODS: LA enhancement in LGE-MRI was quantified in 127 consecutive patients who underwent first time AF ablation. Serial LGE-MRIs were done prior to AF ablation, 3 months postablation and at least 12 months after second LGE-MRI. Transient postablation lesion (TL) was defined as atrial enhancement caused by ablation lesions that was detected on the first (3 month) but not on the second postablation LGE-MRI. New fibrosis (NF) was defined as atrial enhancement detected on the most recent LGE-MRI, at least 15 months after the ablation procedure. AF recurrence and its correlation with TL and NF was assessed in all patients during the follow-up period. RESULTS: An increase of 1% NF increased the chance of postablation AF recurrence by 3% (hazard ratio [HR] 1.03, 95% CI 1-1.06, P = .05). TL had no significant impact on recurrence (P = .057). After adjusting for cardiovascular risk factors, HR increased as NF became greater. Greater volume of NF (≥21%) corresponded with lower arrhythmia-free survival (37% vs 62%, P = .01). CONCLUSION: NF formation postablation of AF is a novel marker of long-term procedural outcome. Extensive NF is associated with significantly higher risk of atrial arrhythmia recurrence.
Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/patologia , Imageamento por Ressonância Magnética/métodos , Idoso , Procedimentos Cirúrgicos Cardíacos/métodos , Estudos de Coortes , Progressão da Doença , Feminino , Fibrose/diagnóstico por imagem , Gadolínio , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos RetrospectivosRESUMO
INTRODUCTION: Multiple markers left atrium (LA) remodeling, including LA shape, correlate with outcomes in atrial fibrillation (AF). Catheter ablation is an important treatment of AF, but better tools are needed to determine which patients will benefit. In this study, we use particle-based modeling to quantitatively assess LA shape, and determine to what degree it predicts AF recurrence after catheter ablation. METHODS AND RESULTS: There were 254 patients enrolled in the DECAAF study who underwent cardiac magnetic resonance imaging of the LA prior to AF ablation and were followed for recurrence for up to 475 days. We performed particle-based shape modeling on each patient's LA shape. We selected shape parameters using the LASSO method and factor analysis, and then added them to a Cox regression model, which included multiple clinical parameters and LA fibrosis. We computed Harrell's C-statistic with and without shape in the model. We used the model to stratify patients into recurrence risk classes by both shape and shape and fibrosis combined. Three shape parameters were selected for inclusion. The C-statistic increased from 0.68 to 0.72 when shape was added to the model (P < 0.05). Visualized shapes showed that a more round LA shape with a shorter, more laterally rotated appendage was predictive of recurrence. CONCLUSION: LA shape is an independent predictor of recurrence after AF ablation. When combined with LA fibrosis, shape analysis using PBM may improve patient selection for ablation.
Assuntos
Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/cirurgia , Remodelamento Atrial , Ablação por Cateter/tendências , Átrios do Coração/diagnóstico por imagem , Imageamento Tridimensional/métodos , Idoso , Remodelamento Atrial/fisiologia , Feminino , Seguimentos , Átrios do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , RecidivaRESUMO
INTRODUCTION: Adequate catheter/atrial tissue contact is critical for lesion formation during radiofrequency (RF) ablation of atrial fibrillation (AF). Late gadolinium enhancement magnetic resonance imaging (LGE-MRI) is a unique tool for the evaluation of lesion formation and detection of acute esophageal injury. METHODS: LGE-MRIs were obtained prior, within 24 hours of, and at 115 ± 62 days after first AF ablation in 36 patients. The Visitag module of CARTO3 was used to collect contact force (CF) and duration from a CF sensing ablation catheter for each registered ablation point. The minimum CF resulting in permanent lesions was determined. Esophageal enhancement detected by acute LGE-MRI was classified as mild, moderate, and severe. The CF resulting in esophageal enhancement was determined. RESULTS: A total of 4,642 registered ablation tags at 50 W power were analyzed. The mean RF duration (5.9 ± 3.7 vs. 5.6 ± 3.2 seconds, P < 0.05), CF (11.5 ± 5.6 vs. 10.9 ± 5.4 g, P < 0.001), and force time integral (FTI) (67.3 ± 54.5 vs. 62.2 ± 52.7 gs, P < 0.01) were significantly higher between ablation tags with and without associated LGE-MRI detected scar. The mean CF (15.7 ± 6.1 vs. 12.6 ± 5.9 g, P < 0.05, n = 17 patients) in areas of esophageal enhancement was greater than areas without. CONCLUSION: Left atrial short duration ablation lesions with a CF greater than 12 g are more likely to be associated with permanent lesion formation. Ablating on top of the esophagus, CF less than 15 g would help minimize esophageal wall injury.
Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter , Meios de Contraste/administração & dosagem , Esôfago/diagnóstico por imagem , Átrios do Coração/cirurgia , Imageamento por Ressonância Magnética , Meglumina/análogos & derivados , Compostos Organometálicos/administração & dosagem , Ferimentos e Lesões/prevenção & controle , Idoso , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/fisiopatologia , Ablação por Cateter/efeitos adversos , Cicatriz/diagnóstico por imagem , Cicatriz/etiologia , Esôfago/lesões , Feminino , Fibrose , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/fisiopatologia , Humanos , Masculino , Meglumina/administração & dosagem , Pessoa de Meia-Idade , Duração da Cirurgia , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Ferimentos e Lesões/diagnóstico por imagem , Ferimentos e Lesões/etiologiaRESUMO
Non-amyloid cerebral small vessel disease (CSVD) and cerebral amyloid angiopathy (CAA) may be interrelated through the damaged basement membranes (BMs) and extracellular matrix changes of small vessels, resulting in a failure of ß-amyloid (Aß) transport and degradation. We analyzed BM changes and the pattern of deposition of Aß in the walls of blood vessels in spontaneously hypertensive stroke-prone rats (SHRSP), a non-transgenic CSVD model. In 45 SHRSP and 38 Wistar rats aged 18 to 32 weeks: (i) the percentage area immunostained for vascular collagen IV and laminin was quantified; (ii) the capillary BM thickness as well as endothelial and pericyte pathological changes were analysed using transmission electron microscopy (TEM); and (iii) the presence of vascular Aß was assessed. Compared with controls, SHRSP exhibited a significantly higher percentage area immunostained with collagen IV in the striatum and thalamus. SHRSP also revealed an age-dependent increase of the capillary BM thickness and of endothelial vacuoles (caveolae) within subcortical regions. Endogenous Aß deposits in the walls of small blood vessels were observed in the cortex (with the highest incidence found within fronto-parietal areas), striatum, thalamus and hippocampus. Vascular ß-amyloid accumulations were frequently detected at sites of small vessel wall damage. Our data demonstrate changes in the expression of collagen IV and of the ultrastructure of BMs in the small vessels of SHRSP. Alterations are accompanied by vascular deposits of endogenous Aß. Impaired ß-amyloid clearance along perivascular and endothelial pathways and failure of extracellular Aß degradation may be the key mechanisms connecting non-amyloid CSVD and CAA.
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Peptídeos beta-Amiloides/metabolismo , Membrana Basal/metabolismo , Doenças de Pequenos Vasos Cerebrais/metabolismo , Microvasos/metabolismo , Animais , Angiopatia Amiloide Cerebral/metabolismo , Modelos Animais de Doenças , Humanos , Ratos , Ratos Endogâmicos SHR , Ratos WistarAssuntos
Oxigenação por Membrana Extracorpórea , Respiração Artificial , Síndrome do Desconforto Respiratório/terapia , Adulto , Oxigenação por Membrana Extracorpórea/efeitos adversos , Humanos , Influenza Humana/complicações , Masculino , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório/etiologiaRESUMO
The diagnosis and severity categorisation of obstructive lung disease is determined using reference values. The American Thoracic Society/European Respiratory Society in 2005 recommended the National Health and Nutrition Examination Survey (NHANES) III spirometry prediction equations for patients in USA aged 8-80â years. The Global Lung Initiative 2012 (GLI 12) provided spirometry prediction equations for patients aged 3-95â years. Comparison of the NHANES III and GLI 12 prediction equations for diagnosing and categorising airway obstruction in patients in USA has not been made.We aimed to quantify the differences between NHANES III and GLI 12 predicted values in Caucasians aged 18-95â years, using both mathematical simulation and clinical data. We compared predicted forced expiratory volume in 1â s (FEV1) and lower limit of normal (LLN) FEV1/forced vital capacity (FVC) % for NHANES III and GLI 12 prediction equations by applying both a simulation model and clinical spirometry data to quantify differences in the diagnosis and categorisation of airway obstruction.Mathematical simulation revealed significant similarities and differences between prediction equations for both LLN FEV1/FVC % and predicted FEV1 There are significant differences when using GLI 12 and NHANES III to diagnose airway obstruction and severity in Caucasian patients aged 18-95â years.Similarities and differences exist between NHANES III and GLI 12 for some age and height combinations. The differences in LLN FEV1/FVC % and predicted FEV1 are most prominent in older taller/shorter individuals. The magnitude of the differences can be large and may result in differences in clinical management.
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Pneumopatias Obstrutivas/classificação , Pneumopatias Obstrutivas/diagnóstico , Pulmão/fisiopatologia , Inquéritos Nutricionais , Espirometria , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Europa (Continente) , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Índice de Gravidade de Doença , Volume de Ventilação Pulmonar , Estados Unidos , População Branca , Adulto JovemRESUMO
The ε4 allele of the apolipoprotein E gene (APOE4) is associated with cognitive decline during aging, is the greatest genetic risk factor for Alzheimer's disease and has links to other neurodegenerative conditions that affect cognition. Increasing evidence indicates that APOE genotypes differentially modulate the function of the cerebrovasculature (CV), with apoE and its receptors expressed by different cell types at the CV interface (astrocytes, pericytes, smooth muscle cells, brain endothelial cells). However, research on the role of apoE in CV dysfunction has not advanced as quickly as other apoE-modulated pathways. This review will assess what aspects of the CV are modulated by APOE genotypes during aging and under disease states, discuss potential mechanisms, and summarize the therapeutic significance of the topic. We propose that APOE4 induces CV dysfunction through direct signaling at the CV, and indirectly via modulation of peripheral and central pathways. Further, that APOE4 predisposes the CV to damage by, and exacerbates the effects of, additional risk factors (such as sex, hypertension, and diabetes). ApoE4-induced detrimental CV changes include reduced cerebral blood flow (CBF), modified neuron-CBF coupling, increased blood-brain barrier leakiness, cerebral amyloid angiopathy, hemorrhages and disrupted transport of nutrients and toxins. The apoE4-induced detrimental changes may be linked to pericyte migration/activation, astrocyte activation, smooth muscle cell damage, basement membrane degradation and alterations in brain endothelial cells.
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Apolipoproteínas E/genética , Transtornos Cerebrovasculares/genética , Predisposição Genética para Doença/genética , Circulação Cerebrovascular/genética , Transtornos Cerebrovasculares/fisiopatologia , HumanosRESUMO
In the absence of conventional lymphatics, drainage of interstitial fluid and solutes from the brain parenchyma to cervical lymph nodes is along basement membranes in the walls of cerebral capillaries and tunica media of arteries. Perivascular pathways are also involved in the entry of CSF into the brain by the convective influx/glymphatic system. The objective of this study is to differentiate the cerebral vascular basement membrane pathways by which fluid passes out of the brain from the pathway by which CSF enters the brain. Experiment 1: 0.5 µl of soluble biotinylated or fluorescent Aß, or 1 µl 15 nm gold nanoparticles was injected into the mouse hippocampus and their distributions determined at 5 min by transmission electron microscopy. Aß was distributed within the extracellular spaces of the hippocampus and within basement membranes of capillaries and tunica media of arteries. Nanoparticles did not enter capillary basement membranes from the extracellular spaces. Experiment 2: 2 µl of 15 nm nanoparticles were injected into mouse CSF. Within 5 min, groups of nanoparticles were present in the pial-glial basement membrane on the outer aspect of cortical arteries between the investing layer of pia mater and the glia limitans. The results of this study and previous research suggest that cerebral vascular basement membranes form the pathways by which fluid passes into and out of the brain but that different basement membrane layers are involved. The significance of these findings for neuroimmunology, Alzheimer's disease, drug delivery to the brain and the concept of the Virchow-Robin space are discussed.
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Membrana Basal/metabolismo , Vasos Sanguíneos/citologia , Hipocampo/metabolismo , Actinas/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/farmacocinética , Animais , Membrana Basal/efeitos dos fármacos , Membrana Basal/ultraestrutura , Biotinilação , Líquido Cefalorraquidiano/efeitos dos fármacos , Líquido Cefalorraquidiano/metabolismo , Cisterna Magna/efeitos dos fármacos , Cisterna Magna/metabolismo , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Corantes Fluorescentes/farmacocinética , Hipocampo/efeitos dos fármacos , Hipocampo/ultraestrutura , Laminina/metabolismo , Masculino , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacocinéticaRESUMO
The lymphatic clearance pathways of the brain are different compared to the other organs of the body and have been the subject of heated debates. Drainage of brain extracellular fluids, particularly interstitial fluid (ISF) and cerebrospinal fluid (CSF), is not only important for volume regulation, but also for removal of waste products such as amyloid beta (Aß). CSF plays a special role in clinical medicine, as it is available for analysis of biomarkers for Alzheimer's disease. Despite the lack of a complete anatomical and physiological picture of the communications between the subarachnoid space (SAS) and the brain parenchyma, it is often assumed that Aß is cleared from the cerebral ISF into the CSF. Recent work suggests that clearance of the brain mainly occurs during sleep, with a specific role for peri- and para-vascular spaces as drainage pathways from the brain parenchyma. However, the direction of flow, the anatomical structures involved and the driving forces remain elusive, with partially conflicting data in literature. The presence of Aß in the glia limitans in Alzheimer's disease suggests a direct communication of ISF with CSF. Nonetheless, there is also the well-described pathology of cerebral amyloid angiopathy associated with the failure of perivascular drainage of Aß. Herein, we review the role of the vasculature and the impact of vascular pathology on the peri- and para-vascular clearance pathways of the brain. The different views on the possible routes for ISF drainage of the brain are discussed in the context of pathological significance.
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Encéfalo/irrigação sanguínea , Encéfalo/patologia , Circulação Cerebrovascular , Linfa/metabolismo , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Animais , Humanos , Modelos Biológicos , Doenças Neurodegenerativas/líquido cefalorraquidianoRESUMO
The American Thoracic Society (ATS) and European Respiratory Society (ERS) recommend that spirometry prediction equations be derived from samples of similar race/ethnicity. Malagasy prediction equations do not exist. The objectives of this study were to establish prediction equations for healthy Malagasy adults, and then compare Malagasy measurements with published prediction equations. We enrolled 2491 healthy Malagasy subjects aged 18-73 years (1428 males) from June 2006 to April 2008. The subjects attempted to meet the ATS/ERS 2005 guidelines when performing forced expiratory spirograms. We compared Malagasy measurements of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with predictions from the European Community for Steel and Coal (ECSC), the third National Health and Nutrition Examination Survey (NHANES III) and the ERS Global Lung Function Initiative (GLI) 2012 study. A linear model for the entire population, using age and height as independent variables, best predicted all spirometry parameters for sea level and highland subjects. FEV1, FVC and FEV1/FVC were most accurately predicted by NHANES III African-American male and female, and by GLI 2012 black male and black and South East Asian female equations. ECSC-predicted FEV1, FVC and FEV1/FVC were poorly matched to Malagasy measurements. We provide the first spirometry reference equations for a healthy adult Malagasy population, and the first comparison of Malagasy population measurements with ECSC, NHANES III and GLI 2012 prediction equations.
Assuntos
Envelhecimento/fisiologia , Volume Expiratório Forçado/fisiologia , Mecânica Respiratória/fisiologia , Espirometria/métodos , Adolescente , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Fatores Etários , Idoso , Antropometria , Estudos de Coortes , Países em Desenvolvimento , Feminino , Voluntários Saudáveis , Humanos , Modelos Lineares , Madagáscar , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Fatores Sexuais , População Branca/estatística & dados numéricos , Adulto JovemRESUMO
OBJECTIVES: In the Fluid and Catheter Treatment Trial (FACTT) of the National Institutes of Health Acute Respiratory Distress Syndrome Network, a conservative fluid protocol (FACTT Conservative) resulted in a lower cumulative fluid balance and better outcomes than a liberal fluid protocol (FACTT Liberal). Subsequent Acute Respiratory Distress Syndrome Network studies used a simplified conservative fluid protocol (FACTT Lite). The objective of this study was to compare the performance of FACTT Lite, FACTT Conservative, and FACTT Liberal protocols. DESIGN: Retrospective comparison of FACTT Lite, FACTT Conservative, and FACTT Liberal. Primary outcome was cumulative fluid balance over 7 days. Secondary outcomes were 60-day adjusted mortality and ventilator-free days through day 28. Safety outcomes were prevalence of acute kidney injury and new shock. SETTING: ICUs of Acute Respiratory Distress Syndrome Network participating hospitals. PATIENTS: Five hundred three subjects managed with FACTT Conservative, 497 subjects managed with FACTT Liberal, and 1,124 subjects managed with FACTT Lite. INTERVENTIONS: Fluid management by protocol. MEASUREMENTS AND MAIN RESULTS: Cumulative fluid balance was 1,918 ± 323 mL in FACTT Lite, -136 ± 491 mL in FACTT Conservative, and 6,992 ± 502 mL in FACTT Liberal (p < 0.001). Mortality was not different between groups (24% in FACTT Lite, 25% in FACTT Conservative and Liberal, p = 0.84). Ventilator-free days in FACTT Lite (14.9 ± 0.3) were equivalent to FACTT Conservative (14.6 ± 0.5) (p = 0.61) and greater than in FACTT Liberal (12.1 ± 0.5, p < 0.001 vs Lite). Acute kidney injury prevalence was 58% in FACTT Lite and 57% in FACTT Conservative (p = 0.72). Prevalence of new shock in FACTT Lite (9%) was lower than in FACTT Conservative (13%) (p = 0.007 vs Lite) and similar to FACTT Liberal (11%) (p = 0.18 vs Lite). CONCLUSIONS: FACTT Lite had a greater cumulative fluid balance than FACTT Conservative but had equivalent clinical and safety outcomes. FACTT Lite is an alternative to FACTT Conservative for fluid management in Acute Respiratory Distress Syndrome.
Assuntos
Hidratação/métodos , Unidades de Terapia Intensiva , Síndrome do Desconforto Respiratório/epidemiologia , Síndrome do Desconforto Respiratório/terapia , Choque/epidemiologia , Pressão Venosa Central , Protocolos Clínicos , Diuréticos/administração & dosagem , Feminino , Furosemida/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição Aleatória , Respiração Artificial/estatística & dados numéricos , Síndrome do Desconforto Respiratório/mortalidade , Estudos Retrospectivos , Choque/mortalidade , Estados Unidos/epidemiologia , Equilíbrio HidroeletrolíticoRESUMO
PURPOSE/AIM: Acute Respiratory Distress Syndrome (ARDS) is an important clinical and public health problem. Why some at-risk individuals develop ARDS and others do not is unclear but may be related to differences in inflammatory and cell signaling systems. The Receptor for Advanced Glycation Endproducts (RAGE) and Granulocyte-Monocyte Stimulating Factor (GM-CSF) pathways have recently been implicated in pulmonary pathophysiology; whether genetic variation within these pathways contributes to ARDS risk or outcome is unknown. MATERIALS AND METHODS: We studied 842 patients from three centers in Utah and 14 non-Utah ARDS Network centers. We studied patients at risk for ARDS and patients with ARDS to determine whether Single Nucleotide Polymorphisms (SNPs) in the RAGE and GM-CSF pathways were associated with development of ARDS. We studied 29 SNPs in 5 genes within the two pathways and controlled for age, sepsis as ARDS risk factor, and severity of illness, while targeting a false discovery rate of ≤ 5%. In a secondary analysis we evaluated associations with mortality. RESULTS: Of 842 patients, 690 had ARDS, and 152 were at-risk. Sepsis was the risk factor for ARDS in 250 (30%) patients. When controlling for age, APACHE III score, sepsis as risk factor, and multiple comparisons, no SNPs were significantly associated with ARDS. In a secondary analysis, only rs743564 in CSF2 approached significance with regard to mortality (OR 2.17, unadjusted p = 0.005, adjusted p = 0.15). CONCLUSIONS: Candidate SNPs within 5 genes in the RAGE and GM-CSF pathways were not significantly associated with development of ARDS in this multi-centric cohort.