Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 62
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Blood Coagul Fibrinolysis ; 31(2): 152-159, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31990754

RESUMO

: Low molecular weight heparins are used during haemodialysis for thromboprophylaxis of the dialysis circuit, with plasma antifactor-Xa (anti-Xa) activity used as a surrogate measure for effective anticoagulation. However, this pharmacokinetic parameter does not always correlate with pharmacodynamic effects in patients. The aim of this study was to investigate the relationship between actual plasma levels of the low molecular weight heparins enoxaparin, anti-Xa activity, and global coagulation measurement of thrombin generation during haemodialysis. Blood was analysed from 16 adult patients with end-stage kidney disease at 0, 2, 4 h, and at completion of 31 dialysis sessions where single fixed doses of 20 (n = 3), 40 (n = 16), 60 (n = 6), or 80 (n = 6) mg of enoxaparin (equating to 0.23-1.07 mg/kg) were used as thromboprophylaxis. Plasma enoxaparin oligosaccharides [degree of polymerization (dp)6-dp16] were measured by high-performance size exclusion chromatography, anti-Xa activity by colourimetric assay, and thrombin generation by calibrated automated thrombogram. Plasma enoxaparin fragments were undetectable at the beginning of each dialysis, peaked at 2 h to levels that correlated with dose (r = 0.68, P < 0.001) then remained relatively stable. In contrast, therapeutic anti-Xa levels achieved at 2 h in 18 cases (58%) quickly dropped to only six cases (19%) at the end of dialysis, by which time thrombin generation had also recovered in 81% of patients. Statistical modelling revealed a threshold value of anti-Xa at 0.53 IU/ml that supressed thrombin generation to 15.28% of baseline (P < 0.001). Despite loss of anticoagulant activity in the majority of patients, plasma levels of enoxaparin oligosaccharides remained detectable and relatively unchanged throughout dialysis.

2.
Crit Care Med ; 48(1): 98-103, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31714399

RESUMO

OBJECTIVES: No consensus exists on a standardized critical care content outline for medical student education. The aim of this research is to develop a national undergraduate medical education critical care content outline. DESIGN: The authors used a Delphi process to reach expert consensus on a content outline that identified the core critical care knowledge topics and procedural skills that medical students should learn prior to entering residency. Over three iterative rounds, the expert panel reached consensus on a critical care content outline. SETTING: An electronic survey of critical care medical educators, residency program directors, and residents in the United States. SUBJECTS: The expert panel included three groups as follows: 1) undergraduate medical education critical care educators, 2) residency program directors representing all core specialties, and 3) residents representing their core specialties. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The expert panel included 28 members. Experts represented the following medical specialties: anesthesiology, emergency medicine, internal medicine, obstetrics and gynecology, pediatrics, and surgery. Seventeen experts had subspecialty training in critical care. The expert panel identified 19 highly recommended critical care knowledge topics and procedural skills. These topics and procedural skills were grouped into five broad categories as follows: 1) neurologic, 2) respiratory, 3) cardiovascular, 4) renal and electrolytes, and 5) supplemental ICU topics. Bag-mask ventilation was the only procedural skill identified as highly recommended. CONCLUSIONS: This study provides a national consensus undergraduate medical education critical care content outline. By including experts from multiple specialties, this content outline is meaningful for medical student education, independent of medical specialty. The content outline represents a first step in the development of a national undergraduate medical education critical care curriculum.

3.
Proc Natl Acad Sci U S A ; 116(49): 24748-24759, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31748275

RESUMO

Peptides generated by proteasome-catalyzed splicing of noncontiguous amino acid sequences have been shown to constitute a source of nontemplated human leukocyte antigen class I (HLA-I) epitopes, but their role in pathogen-specific immunity remains unknown. CD8+ T cells are key mediators of HIV type 1 (HIV-1) control, and identification of novel epitopes to enhance targeting of infected cells is a priority for prophylactic and therapeutic strategies. To explore the contribution of proteasome-catalyzed peptide splicing (PCPS) to HIV-1 epitope generation, we developed a broadly applicable mass spectrometry-based discovery workflow that we employed to identify spliced HLA-I-bound peptides on HIV-infected cells. We demonstrate that HIV-1-derived spliced peptides comprise a relatively minor component of the HLA-I-bound viral immunopeptidome. Although spliced HIV-1 peptides may elicit CD8+ T cell responses relatively infrequently during infection, CD8+ T cells primed by partially overlapping contiguous epitopes in HIV-infected individuals were able to cross-recognize spliced viral peptides, suggesting a potential role for PCPS in restricting HIV-1 escape pathways. Vaccine-mediated priming of responses to spliced HIV-1 epitopes could thus provide a novel means of exploiting epitope targets typically underutilized during natural infection.

4.
Lancet Respir Med ; 7(11): 964-974, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31562059

RESUMO

BACKGROUND: Pneumonia is the leading cause of death among children globally. Most pneumonia deaths in low-income and middle-income countries (LMICs) occur among children with HIV infection or exposure, severe malnutrition, or hypoxaemia despite antibiotics and oxygen. Non-invasive bubble continuous positive airway pressure (bCPAP) is considered a safe ventilation modality that might improve child pneumonia survival. bCPAP outcomes for high-risk African children with severe pneumonia are unknown. Since most child pneumonia hospitalisations in Africa occur in non-tertiary district hospitals without daily physician oversight, we aimed to examine whether bCPAP improves severe pneumonia mortality in such settings. METHODS: This open-label, randomised, controlled trial was done in the general paediatric ward of Salima District Hospital, Malawi. We enrolled children aged 1-59 months old with WHO-defined severe pneumonia and either HIV infection or exposure, severe malnutrition, or an oxygen saturation of less than 90%. Children were randomly assigned 1:1 to low-flow nasal cannula oxygen or nasal bCPAP. Non-physicians administered care; the primary outcome was hospital survival. Primary analyses were by intention-to-treat and interim and adverse events analyses per protocol. This trial is registered with ClinicalTrials.gov, number NCT02484183, and is closed. FINDINGS: We screened 1712 children for eligibility between June 23, 2015, and March 21, 2018. The data safety and monitoring board stopped the trial for futility after 644 of the intended 900 participants were enrolled. 323 children were randomly assigned to oxygen and 321 to bCPAP. 35 (11%) of 323 children who received oxygen died in hospital, as did 53 (17%) of 321 who received bCPAP (relative risk 1·52; 95% CI 1·02-2·27; p=0·036). 13 oxygen and 17 bCPAP patients lacked hospital outcomes and were considered lost to follow-up. Suspected adverse events related to treatment occurred in 11 (3%) of 321 children receiving bCPAP and 1 (<1%) of 323 children receiving oxygen. Four bCPAP and one oxygen group deaths were classified as probable aspiration episodes, one bCPAP death as probable pneumothorax, and six non-death bCPAP events included skin breakdown around the nares. INTERPRETATION: bCPAP treatment in a paediatric ward without daily physician supervision did not reduce hospital mortality among high-risk Malawian children with severe pneumonia, compared with oxygen. The use of bCPAP within certain patient populations and non-intensive care settings might carry risk that was not previously recognised. bCPAP in LMICs needs further evaluation before wider implementation for child pneumonia care. FUNDING: Bill & Melinda Gates Foundation, International AIDS Society, Health Empowering Humanity.

5.
BMC Health Serv Res ; 19(1): 533, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366394

RESUMO

BACKGROUND: In some low-resource settings bubble continuous positive airway pressure (bCPAP) is increasingly used to treat children with pneumonia. However, the time required for healthcare workers (HCWs) to administer bCPAP is unknown and may have implementation implications. This study aims to compare HCW time spent administering bCPAP and low-flow nasal oxygen care at a district hospital in Malawi during CPAP IMPACT (Improving Mortality for Pneumonia in African Children Trial). METHODS: Eligible participants were 1-59 months old with WHO-defined severe pneumonia and HIV-infection, HIV-exposure, severe malnutrition, or hypoxemia and were randomized to either bCPAP or oxygen. We used time motion techniques to observe hospital care in four hour blocks during treatment initiation or follow up (maintenance). HCW mean time per patient at the bedside over the observation period was calculated by study arm. RESULTS: Overall, bCPAP required an average of 34.71 min per patient more than low-flow nasal oxygen to initiate (bCPAP, 118.18 min (standard deviation (SD) 42.73 min); oxygen, 83.47 min (SD, 20.18 min), p < 0.01). During initiation, HCWs spent, on average, 12.45 min longer per patient setting up bCPAP equipment (p < 0.01) and 11.13 min longer per patient setting up the bCPAP nasal interface (p < 0.01), compared to oxygen equipment and nasal cannula set-up. During maintenance care, HCWs spent longer on average per patient adjusting bCPAP, compared to oxygen equipment (bCPAP 4.57 min (SD, 4.78 min); oxygen, 1.52 min (SD, 2.50 min), p = 0.03). CONCLUSION: Effective bCPAP implementation in low-resource settings will likely create additional HCW burden relative to usual pneumonia care with oxygen. TRIAL REGISTRATION: Clinicaltrials.gov NCT02484183 , June 29, 2015.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas/métodos , Corpo Clínico Hospitalar , Oxigenoterapia/métodos , Pneumonia/terapia , Carga de Trabalho/estatística & dados numéricos , Pré-Escolar , Feminino , Pesquisa sobre Serviços de Saúde , Hospitais de Distrito , Humanos , Lactente , Malaui/epidemiologia , Masculino , Pneumonia/mortalidade , Fatores de Tempo , Estudos de Tempo e Movimento
6.
J Adolesc Young Adult Oncol ; 8(5): 529-533, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31150299

RESUMO

Pain is an understudied and undertreated consequence of cancer survival. Pain education is now a recommended treatment approach for persistent non-cancer pain, yet it has not been well applied to the context of adolescent and young adult (AYA) cancer survival. In March 2018, an interdisciplinary meeting was held in Adelaide, South Australia to set a research agenda for pain education in AYA cancer survivors. We identified that AYAs with persistent pain and those with heightened pain-related fear have the potential to benefit from pain education. We identified a number of unique challenges of engaging AYA survivors in pain education, and point towards future research directions.

7.
Proc Natl Acad Sci U S A ; 116(8): 3229-3238, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30718403

RESUMO

Human and simian immunodeficiency viruses (HIV/SIVs) use CD4 as the primary receptor to enter target cells. Here, we show that the chimpanzee CD4 is highly polymorphic, with nine coding variants present in wild populations, and that this diversity interferes with SIV envelope (Env)-CD4 interactions. Testing the replication fitness of SIVcpz strains in CD4+ T cells from captive chimpanzees, we found that certain viruses were unable to infect cells from certain hosts. These differences were recapitulated in CD4 transfection assays, which revealed a strong association between CD4 genotypes and SIVcpz infection phenotypes. The most striking differences were observed for three substitutions (Q25R, Q40R, and P68T), with P68T generating a second N-linked glycosylation site (N66) in addition to an invariant N32 encoded by all chimpanzee CD4 alleles. In silico modeling and site-directed mutagenesis identified charged residues at the CD4-Env interface and clashes between CD4- and Env-encoded glycans as mechanisms of inhibition. CD4 polymorphisms also reduced Env-mediated cell entry of monkey SIVs, which was dependent on at least one D1 domain glycan. CD4 allele frequencies varied among wild chimpanzees, with high diversity in all but the western subspecies, which appeared to have undergone a selective sweep. One allele was associated with lower SIVcpz prevalence rates in the wild. These results indicate that substitutions in the D1 domain of the chimpanzee CD4 can prevent SIV cell entry. Although some SIVcpz strains have adapted to utilize these variants, CD4 diversity is maintained, protecting chimpanzees against infection with SIVcpz and other SIVs to which they are exposed.


Assuntos
Antígenos CD4/genética , Síndrome de Imunodeficiência Adquirida dos Símios/genética , Vírus da Imunodeficiência Símia/genética , Proteínas do Envelope Viral/genética , Animais , Antígenos CD4/imunologia , Linfócitos T CD4-Positivos/imunologia , Evolução Molecular , Variação Genética/imunologia , HIV/genética , HIV/patogenicidade , Humanos , Pan troglodytes/genética , Pan troglodytes/imunologia , Polissacarídeos/genética , Polissacarídeos/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/patogenicidade , Proteínas do Envelope Viral/imunologia
8.
J Emerg Med ; 56(1): e5-e8, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30420308

RESUMO

BACKGROUND: Inborn errors of metabolism (IEM) commonly present in infancy and, less commonly, later in life. CASE REPORT: This case describes an IEM, specifically, ornithine transcarbamylase deficiency, in a previously healthy 7-year-old boy who presented to an emergency department with vomiting for approximately 24 h prior to admission. The child became progressively encephalopathic while in the emergency department, but an ammonia level was not obtained until several hours after admission. Irreversible brain damage with cerebral edema was already present at time of diagnosis, leading to death. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case emphasizes that acute hyperammonemia can rapidly cause irreversible neurological damage and, in the case of a newly encephalopathic pediatric patient, ammonia levels should be evaluated early to facilitate proper diagnostic tests and treatment.


Assuntos
Encefalopatias/etiologia , Doença da Deficiência de Ornitina Carbomoiltransferase/complicações , Amônia/análise , Amônia/sangue , Encefalopatias/diagnóstico , Criança , Diagnóstico Tardio , Delírio/etiologia , Serviço Hospitalar de Emergência/organização & administração , Humanos , Hiperamonemia/sangue , Hiperamonemia/diagnóstico , Masculino , Erros Inatos do Metabolismo/complicações , Doença da Deficiência de Ornitina Carbomoiltransferase/diagnóstico , Vômito/etiologia
9.
Cell Rep ; 25(4): 893-908.e7, 2018 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-30355496

RESUMO

Densely arranged N-linked glycans shield the HIV-1 envelope (Env) trimer from antibody recognition. Strain-specific breaches in this shield (glycan holes) can be targets of vaccine-induced neutralizing antibodies that lack breadth. To understand the interplay between glycan holes and neutralization breadth in HIV-1 infection, we developed a sequence- and structure-based approach to identify glycan holes for individual Env sequences that are shielded in most M-group viruses. Applying this approach to 12 longitudinally followed individuals, we found that transmitted viruses with more intact glycan shields correlated with development of greater neutralization breadth. Within 2 years, glycan acquisition filled most glycan holes present at transmission, indicating escape from hole-targeting neutralizing antibodies. Glycan hole filling generally preceded the time to first detectable breadth, although time intervals varied across hosts. Thus, completely glycan-shielded viruses were associated with accelerated neutralization breadth development, suggesting that Env immunogens with intact glycan shields may be preferred components of AIDS vaccines.


Assuntos
Anticorpos Neutralizantes/metabolismo , HIV-1/metabolismo , Polissacarídeos/metabolismo , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo , Biologia Computacional , Sequência Conservada , Células HEK293 , Humanos , Cinética , Modelos Moleculares , Testes de Neutralização , Polissacarídeos/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/química
10.
Ecol Evol ; 8(16): 7946-7963, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30250675

RESUMO

Short tandem repeats (STRs), also known as microsatellites, are commonly used to noninvasively genotype wild-living endangered species, including African apes. Until recently, capillary electrophoresis has been the method of choice to determine the length of polymorphic STR loci. However, this technique is labor intensive, difficult to compare across platforms, and notoriously imprecise. Here we developed a MiSeq-based approach and tested its performance using previously genotyped fecal samples from long-term studied chimpanzees in Gombe National Park, Tanzania. Using data from eight microsatellite loci as a reference, we designed a bioinformatics platform that converts raw MiSeq reads into locus-specific files and automatically calls alleles after filtering stutter sequences and other PCR artifacts. Applying this method to the entire Gombe population, we confirmed previously reported genotypes, but also identified 31 new alleles that had been missed due to sequence differences and size homoplasy. The new genotypes, which increased the allelic diversity and heterozygosity in Gombe by 61% and 8%, respectively, were validated by replicate amplification and pedigree analyses. This demonstrated inheritance and resolved one case of an ambiguous paternity. Using both singleplex and multiplex locus amplification, we also genotyped fecal samples from chimpanzees in the Greater Mahale Ecosystem in Tanzania, demonstrating the utility of the MiSeq-based approach for genotyping nonhabituated populations and performing comparative analyses across field sites. The new automated high-throughput analysis platform (available at https://github.com/ShawHahnLab/chiimp) will allow biologists to more accurately and effectively determine wildlife population size and structure, and thus obtain information critical for conservation efforts.

11.
Toxicol Res (Camb) ; 7(4): 647-663, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30090612

RESUMO

The haem biosynthetic pathway is of fundamental importance for cellular metabolism both for the erythroid and nonerythroid tissues. There are several genetic variants of the pathway in the human population that cause dysfunction of one or other of the enzymes resulting in porphyrias of varying severity. Serious chronic hepatic and systemic diseases may result. Some of these can be precipitated by exposure to drugs including hormones, barbiturates and antibiotics, as well as alcohol and particular chlorinated aromatic chemicals. In experimental animals some of the steps of this pathway can also be severely disrupted by a variety of environmental chemicals, potential drugs and pesticides, especially in the liver, leading to the accumulation of uroporphyrins derived from the intermediate uroporphyrinogens or protoporphyrin IX, the immediate precursor of haem. With some of these chemicals this also leads to cholestasis and liver cell injury and eventually hepatic tumours. The review evaluates the available evidence linking hepatic porphyria with carcinogenesis in naturally occurring human genetic conditions and in chemically-induced porphyrias in laboratory animals. The existing data showing gender, strain, and species differences in sensitivity to the chemical-induced porphyrias, liver injury and liver tumours are discussed and the role that transgenically altered mouse models have played in defining the varying mechanisms. Finally, the review proposes a novel, unifying hypothesis linking the hepatotoxicity induced by the accumulation of various porphyrins, with the increased risk of developing hepatic cancer as a long term consequence.

12.
Dalton Trans ; 47(27): 9030-9037, 2018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-29927448

RESUMO

We report an efficient, one-step synthesis of the chelator 3-hydroxy-2-methyl-4-selenopyrone (selenomaltol). Complexes of selenomaltol with Fe(iii), Ni(ii), Cu(ii) and Zn(ii) have been prepared and studied by NMR, X-ray crystallography, cyclic voltammetry, EPR and electronic absorption. The Ni(ii) and Cu(ii) complexes show chemically reversible oxidations which are suggested to be ligand-based. Nuclear independent chemical shifts (NICS) analysis is used to compare aromaticity of the heterocyclic rings of selenomaltol and its chelates. The compounds described here should significantly expand the scope and utility of unusual O,Se-donor chelates.

13.
Bone ; 109: 56-60, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29320714

RESUMO

Mesenteric heterotopic ossification (MHO) is very rare and occurs in mid- to late-adulthood, usually in the context of prior abdominal surgery. The mechanisms of MHO are unknown. Here we describe the case of a 72-year-old man with MHO. Standard histological staining revealed that MHO occurred through an endochondral process. By comparison to known mutations in genetic conditions of HO such as fibrodysplasia ossificans progressiva (FOP) and progressive osseous heteroplasia (POH), DNA sequencing analysis demonstrated the presence of a commonly occurring heterozygous synonymous polymorphism (c.690G>A; E230E) in the causative gene for FOP (ACVR1/ALK2). However, no frameshift, missense, or nonsense mutations in ACVR1, or in the causative gene for POH (GNAS), were found. Although genetic predisposition may play a role in MHO, our data suggest that mutations which occur in known hereditary conditions of HO are not the primary cause.


Assuntos
Ossificação Heterotópica/genética , Ossificação Heterotópica/patologia , Idoso , Doenças Ósseas Metabólicas/genética , Doenças Ósseas Metabólicas/patologia , Predisposição Genética para Doença , Humanos , Masculino , Miosite Ossificante/genética , Miosite Ossificante/patologia , Análise de Sequência de DNA , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/patologia
15.
BMJ Open Respir Res ; 4(1): e000195, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28883928

RESUMO

INTRODUCTION: Pneumonia is a leading cause of mortality among children in low-resource settings. Mortality is greatest among children with high-risk conditions including HIV infection or exposure, severe malnutrition and/or severe hypoxaemia. WHO treatment recommendations include low-flow oxygen for children with severe pneumonia. Bubble continuous positive airway pressure (bCPAP) is a non-invasive support modality that provides positive end-expiratory pressure and oxygen. bCPAP is effective in the treatment of neonates in low-resource settings; its efficacy is unknown for high-risk children with severe pneumonia in low-resource settings. METHODS AND ANALYSIS: CPAP IMPACT is a randomised clinical trial comparing bCPAP to low-flow oxygen in the treatment of severe pneumonia among high-risk children 1-59 months of age. High-risk children are stratified into two subgroups: (1) HIV infection or exposure and/or severe malnutrition; (2) severe hypoxaemia. The trial is being conducted in a Malawi district hospital and will enrol 900 participants. The primary outcome is in-hospital mortality rate of children treated with standard care as compared with bCPAP. ETHICS AND DISSEMINATION: CPAP IMPACT has approval from the Institutional Review Boards of all investigators. An urgent need exists to determine whether bCPAP decreases mortality among high-risk children with severe pneumonia to inform resource utilisation in low-resource settings. TRIAL REGISTRATION NUMBER: NCT02484183; Pre-results.

16.
Math Biosci ; 291: 46-55, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28709974

RESUMO

Populations often exist, either by choice or by external pressure, in a fragmented way, referred to as a metapopulation. Typically, the dynamics accounted for within metapopulation models are assumed to be static. For example, patch occupancy models often assume that the colonisation and extinction rates do not change, while spatially structured models often assume that the rates of births, deaths and migrations do not depend on time. While some progress has been made when these dynamics are changing deterministically, less is known when the changes are stochastic. It can be quite common that the environment a population inhabits determines how these dynamics change over time. Changes to this environment can have a large impact on the survival probability of a population and such changes will often be stochastic. The typical metapopulation model allows for catastrophes that could eradicate most, if not all, individuals on an entire patch. It is this type of phenomenon that this article addresses. A Markov process is developed that models the number of individuals on each patch within a metapopulation. An approximation for the original model is presented in the form of a piecewise-deterministic Markov process and the approximation is analysed to present conditions for extinction.


Assuntos
Meio Ambiente , Cadeias de Markov , Dinâmica Populacional , Humanos , Modelos Teóricos , Processos Estocásticos
17.
Proc Natl Acad Sci U S A ; 114(4): E590-E599, 2017 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-28069935

RESUMO

Sexual transmission of HIV-1 is an inefficient process, with only one or few variants of the donor quasispecies establishing the new infection. A critical, and as yet unresolved, question is whether the mucosal bottleneck selects for viruses with increased transmission fitness. Here, we characterized 300 limiting dilution-derived virus isolates from the plasma, and in some instances genital secretions, of eight HIV-1 donor and recipient pairs. Although there were no differences in the amount of virion-associated envelope glycoprotein, recipient isolates were on average threefold more infectious (P = 0.0001), replicated to 1.4-fold higher titers (P = 0.004), were released from infected cells 4.2-fold more efficiently (P < 0.00001), and were significantly more resistant to type I IFNs than the corresponding donor isolates. Remarkably, transmitted viruses exhibited 7.8-fold higher IFNα2 (P < 0.00001) and 39-fold higher IFNß (P < 0.00001) half-maximal inhibitory concentrations (IC50) than did donor isolates, and their odds of replicating in CD4+ T cells at the highest IFNα2 and IFNß doses were 35-fold (P < 0.00001) and 250-fold (P < 0.00001) greater, respectively. Interestingly, pretreatment of CD4+ T cells with IFNß, but not IFNα2, selected donor plasma isolates that exhibited a transmitted virus-like phenotype, and such viruses were also detected in the donor genital tract. These data indicate that transmitted viruses are phenotypically distinct, and that increased IFN resistance represents their most distinguishing property. Thus, the mucosal bottleneck selects for viruses that are able to replicate and spread efficiently in the face of a potent innate immune response.


Assuntos
Infecções por HIV/imunologia , Infecções por HIV/transmissão , HIV-1/fisiologia , Interferon Tipo I/imunologia , Feminino , Interações Hospedeiro-Patógeno , Humanos , Masculino , Sêmen/virologia , Ducha Vaginal , Vírion , Replicação Viral
18.
Math Biosci ; 268: 38-44, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26260102

RESUMO

A new functional law of large numbers to approximate a time inhomogeneous Markov process that is only density dependent in the limit as an index parameter goes to infinity is developed. This extends previous results by other authors to a broader class of Markov processes while relaxing some of the conditions required for those results to hold. This result is applied to a stochastic metapopulation model that accounts for spatial structure as well as within patch dynamics with the novel addition of time dependent dynamics. The resulting nonautonomous differential equation is analysed to provide conditions for extinction and persistence for a number of examples. This condition shows that the migration of a species will positively impact the reproduction in less populated areas while negatively impacting densely populated areas.


Assuntos
Ecossistema , Cadeias de Markov , Modelos Teóricos , Densidade Demográfica , Dinâmica Populacional
19.
Pediatrics ; 135(4): 694-700, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25802343

RESUMO

BACKGROUND: Pediatric palliative care (PPC) improves the quality of life for children with life-limiting conditions, but the cost of care associated with PPC has not been quantified. This study examined the association between inpatient cost and receipt of PPC among high-cost inpatients. METHODS: The 10% most costly inpatients treated at a children's hospital in 2010 were studied, and factors associated with receipt of PPC were determined. Among patients dying during 2010, we compared 2010 inpatient costs between PPC recipients and nonrecipients. Inpatient costs during the 2-year follow up period between PPC recipients and nonrecipients were also compared. Patients were analyzed in 2 groups: those who died and those who survived the 2-year follow-up. RESULTS: Of 902 patients, 86 (10%) received PPC. Technology dependence, older age, multiple chronic conditions, PICU admission, and death in 2010 were independently associated with receipt of PPC. PPC recipients had increased inpatient costs compared with nonrecipients during 2010. Among patients who died during the 2-year follow-up, PPC recipients had significantly lower inpatient costs. Among survivors, PPC recipients had greater inpatient costs. When controlling for patient complexity, differences in inpatient costs were not significant. CONCLUSIONS: The relationship of PPC to inpatient costs is complex. PPC seems to lower costs among patients approaching death. Patients selectively referred to PPC who survive most often do so with chronic serious illnesses that predispose them to remain lifelong high-resource utilizers.


Assuntos
Custos Hospitalares/estatística & dados numéricos , Hospitalização/economia , Programas Nacionais de Saúde/economia , Cuidados Paliativos/economia , Pediatria/economia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Doença Crônica/economia , Doença Crônica/terapia , Estudos de Coortes , Feminino , Mortalidade Hospitalar , Hospitais Pediátricos/economia , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Pediátrica/economia , Tempo de Internação/economia , Estudos Longitudinais , Masculino , Determinação de Necessidades de Cuidados de Saúde/economia , Equipe de Assistência ao Paciente/economia , Assistência Terminal/economia
20.
PLoS One ; 9(9): e106955, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25203682

RESUMO

The aryl hydrocarbon receptor (AhR) has been shown to be required for optimal Thelper (Th) 17 cell activation. Th17 cells provide immunity against extracellular pathogens and are implicated in autoimmune diseases. Herein, the role of the AhR in cytokine production by Th17, and by the analogous population of T cytotoxic (Tc)17 cells, has been examined. Lymph node Tc (CD8(+)) and Th (CD4(+)) cells were isolated by negative selection from naive AhR(+/-) and AhR(-/-) mice and polarised to Tc1/Th1 or Tc17/Th17 phenotypes with appropriate cytokines. Cell differentiation was assessed as a function of mRNA and protein (ELISA and flow cytometry) expression for interferon (IFN)-γ and for key Th17 cytokines. In AhR(+/-) mice, Th17 cells displayed an exclusive IL-17 profile, which was markedly inhibited by a selective AhR antagonist to levels observed in AhR knockout mice. Addition of the natural AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ) markedly enhanced Th17 cell activity in the heterozygotes. In contrast, Tc17 cells polarised into 3 distinct subsets: producing either IL-17 or IFN-γ alone, or both cytokines. Blocking AhR was also detrimental to Tc17 development, with reduced responses recorded in AhR(-/-) mice and antagonist-mediated reduction of IL-17 expression in the heterozygotes. However, Tc17 cells were largely refractory to exogenous FICZ, presumably because Tc17 cells express baseline AhR mRNA, but unlike Th17 cells, there is no marked up-regulation during polarisation. Thus, Th17 cell development is more dependent upon AhR activation than is Tc17 cell development, suggesting that endogenous AhR ligands play a much greater role in driving Th17 cell responses.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Linfócitos T Citotóxicos/citologia , Células Th17/citologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Feminino , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Interleucina-17/biossíntese , Interleucina-17/genética , Interleucinas/biossíntese , Interleucinas/genética , Cinética , Masculino , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Hidrocarboneto Arílico/deficiência , Receptores de Hidrocarboneto Arílico/genética , Linfócitos T Citotóxicos/metabolismo , Células Th17/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA