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2.
J Virol ; 93(4)2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30541831

RESUMO

Respiratory syncytial virus (RSV) is a leading cause of hospitalization of infants and young children, causing considerable respiratory disease and repeat infections that may lead to chronic respiratory conditions such as asthma, wheezing, and bronchitis. RSV causes ∼34 million new episodes of lower respiratory tract illness (LRTI) in children younger than 5 years of age, with >3 million hospitalizations due to severe RSV-associated LRTI. The standard of care is limited to symptomatic relief as there are no approved vaccines and few effective antiviral drugs; thus, a safe and efficacious RSV therapeutic is needed. Therapeutic targeting of host proteins hijacked by RSV to facilitate replication is a promising antiviral strategy as targeting the host reduces the likelihood of developing drug resistance. The nuclear export of the RSV M protein, mediated by the nuclear export protein exportin 1 (XPO1), is crucial for RSV assembly and budding. Inhibition of RSV M protein export by leptomycin B correlated with reduced RSV replication in vitro In this study, we evaluated the anti-RSV efficacy of Verdinexor (KPT-335), a small molecule designed to reversibly inhibit XPO1-mediated nuclear export. KPT-335 inhibited XPO1-mediated transport and reduced RSV replication in vitro KPT-335 was effective against RSV A and B strains and reduced viral replication following prophylactic or therapeutic administration. Inhibition of RSV replication by KPT-335 was due to a combined effect of reduced XPO1 expression, disruption of the nuclear export of RSV M protein, and inactivation of the NF-κB signaling pathway.IMPORTANCE RSV is an important cause of LRTI in infants and young children for which there are no suitable antiviral drugs offered. We evaluated the efficacy of KPT-335 as an anti-RSV drug and show that KPT-335 inhibits XPO1-mediated nuclear export, leading to nuclear accumulation of RSV M protein and reduction in RSV levels. KPT-335 treatment also resulted in inhibition of proinflammatory pathways, which has important implications for its effectiveness in vivo.

3.
Ann Surg ; 268(2): 357-363, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28486392

RESUMO

OBJECTIVE: To determine the prognostic relevance, clinical characteristics, and 30-day outcomes associated with myocardial injury after noncardiac surgery (MINS) in vascular surgical patients. BACKGROUND: MINS has been independently associated with 30-day mortality after noncardiac surgery. The characteristics and prognostic importance of MINS in vascular surgery patients are poorly described. METHODS: This was an international prospective cohort study of 15,102 noncardiac surgery patients 45 years or older, of whom 502 patients underwent vascular surgery. All patients had fourth-generation plasma troponin T (TnT) concentrations measured during the first 3 postoperative days. MINS was defined as a TnT of 0.03 ng/mL of higher secondary to ischemia. The objectives of the present study were to determine (i) if MINS is prognostically important in vascular surgical patients, (ii) the clinical characteristics of vascular surgery patients with and without MINS, (iii) the 30-day outcomes for vascular surgery patients with and without MINS, and (iv) the proportion of MINS that probably would have gone undetected without routine troponin monitoring. RESULTS: The incidence of MINS in the vascular surgery patients was 19.1% (95% confidence interval (CI), 15.7%-22.6%). 30-day all-cause mortality in the vascular cohort was 12.5% (95% CI 7.3%-20.6%) in patients with MINS compared with 1.5% (95% CI 0.7%-3.2%) in patients without MINS (P < 0.001). MINS was independently associated with 30-day mortality in vascular patients (odds ratio, 9.48; 95% CI, 3.46-25.96). The 30-day mortality was similar in MINS patients with (15.0%; 95% CI, 7.1-29.1) and without an ischemic feature (12.2%; 95% CI, 5.3-25.5, P = 0.76). The proportion of vascular surgery patients who suffered MINS without overt evidence of myocardial ischemia was 74.1% (95% CI, 63.6-82.4). CONCLUSIONS: Approximately 1 in 5 patients experienced MINS after vascular surgery. MINS was independently associated with 30-day mortality. The majority of patients with MINS were asymptomatic and would have gone undetected without routine postoperative troponin measurement.

4.
Health Policy ; 121(10): 1053-1062, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28867153

RESUMO

The aim of this paper is to explain informal payments by patients to healthcare professionals for the first time through the lens of institutional theory as arising when there are formal institutional imperfections and asymmetry between norms, values and practices and the codified formal laws and regulations. Reporting a 2013 Eurobarometer survey of the prevalence of informal payments by patients in 28 European countries, a strong association is revealed between the degree to which formal and informal institutions are unaligned and the propensity to make informal payments. The association between informal payments and formal institutional imperfections is then explored to evaluate which structural conditions might reduce this institutional asymmetry, and thus the propensity to make informal payments. The paper concludes by exploring the implications for tackling such informal practices.


Assuntos
Assistência à Saúde/economia , Financiamento Pessoal/estatística & dados numéricos , Adolescente , Adulto , Cultura , Assistência à Saúde/normas , União Europeia , Feminino , Gastos em Saúde/estatística & dados numéricos , Política de Saúde , Humanos , Masculino , Pessoa de Meia-Idade
5.
JAMA ; 317(16): 1642-1651, 2017 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-28444280

RESUMO

Importance: Little is known about the relationship between perioperative high-sensitivity troponin T (hsTnT) measurements and 30-day mortality and myocardial injury after noncardiac surgery (MINS). Objective: To determine the association between perioperative hsTnT measurements and 30-day mortality and potential diagnostic criteria for MINS (ie, myocardial injury due to ischemia associated with 30-day mortality). Design, Setting, and Participants: Prospective cohort study of patients aged 45 years or older who underwent inpatient noncardiac surgery and had a postoperative hsTnT measurement. Starting in October 2008, participants were recruited at 23 centers in 13 countries; follow-up finished in December 2013. Exposures: Patients had hsTnT measurements 6 to 12 hours after surgery and daily for 3 days; 40.4% had a preoperative hsTnT measurement. Main Outcomes and Measures: A modified Mazumdar approach (an iterative process) was used to determine if there were hsTnT thresholds associated with risk of death and had an adjusted hazard ratio (HR) of 3.0 or higher and a risk of 30-day mortality of 3% or higher. To determine potential diagnostic criteria for MINS, regression analyses ascertained if postoperative hsTnT elevations required an ischemic feature (eg, ischemic symptom or electrocardiography finding) to be associated with 30-day mortality. Results: Among 21 842 participants, the mean age was 63.1 (SD, 10.7) years and 49.1% were female. Death within 30 days after surgery occurred in 266 patients (1.2%; 95% CI, 1.1%-1.4%). Multivariable analysis demonstrated that compared with the reference group (peak hsTnT <5 ng/L), peak postoperative hsTnT levels of 20 to less than 65 ng/L, 65 to less than 1000 ng/L, and 1000 ng/L or higher had 30-day mortality rates of 3.0% (123/4049; 95% CI, 2.6%-3.6%), 9.1% (102/1118; 95% CI, 7.6%-11.0%), and 29.6% (16/54; 95% CI, 19.1%-42.8%), with corresponding adjusted HRs of 23.63 (95% CI, 10.32-54.09), 70.34 (95% CI, 30.60-161.71), and 227.01 (95% CI, 87.35-589.92), respectively. An absolute hsTnT change of 5 ng/L or higher was associated with an increased risk of 30-day mortality (adjusted HR, 4.69; 95% CI, 3.52-6.25). An elevated postoperative hsTnT (ie, 20 to <65 ng/L with an absolute change ≥5 ng/L or hsTnT ≥65 ng/L) without an ischemic feature was associated with 30-day mortality (adjusted HR, 3.20; 95% CI, 2.37-4.32). Among the 3904 patients (17.9%; 95% CI, 17.4%-18.4%) with MINS, 3633 (93.1%; 95% CI, 92.2%-93.8%) did not experience an ischemic symptom. Conclusions and Relevance: Among patients undergoing noncardiac surgery, peak postoperative hsTnT during the first 3 days after surgery was significantly associated with 30-day mortality. Elevated postoperative hsTnT without an ischemic feature was also associated with 30-day mortality.


Assuntos
Infarto do Miocárdio/mortalidade , Isquemia Miocárdica/mortalidade , Troponina T/sangue , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Período Pós-Operatório , Estudos Prospectivos , Medição de Risco
6.
Lab Anim (NY) ; 45(9): 333-7, 2016 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-27551803

RESUMO

Cotton rats (Sigmodon hispidus) are widely used as animal models for infectious disease and immunological research. They emulate many aspects of human disease pathogenesis, and the introduction of cotton rat-specific immunological reagents, cell lines and sequencing of relevant genes have all helped to increase the popularity of this disease model. However, the use of cotton rats is problematic owing to their propensity for aggressive responses when handled, which can lead to escape, increased stress to the animals, and bites to staff. When cotton rats are co-housed, which is recommended under current social housing guidelines, these risks are increased. Here, we describe a method of isoflurane anesthesia induction in the home cage that reduces the risk of animal escape, minimizes stress during induction, and provides additional safety for staff. The method uses inexpensive materials that are widely available and can be easily disinfected. Our method also eliminates the need for expensive and cumbersome machines traditionally used with anesthetic chambers, and uses a minimal amount of inhalant anesthetic, saving resources and protecting staff from inhalation of leaked gas.


Assuntos
Anestesia/veterinária , Anestésicos Inalatórios/administração & dosagem , Isoflurano/administração & dosagem , Sigmodontinae , Anestesia/métodos , Animais , Feminino
8.
Arch Sex Behav ; 45(7): 1665-78, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27091188

RESUMO

This research investigates the sexuality of trans women (individuals who were assigned male status at birth who currently identify as women), by focusing on the "bodily techniques" (Crossley, 2006) they use in "doing" sexuality. The "doing sexuality" framework not only is modeled after the "doing gender" approach of West and Zimmerman (1987), but also utilizes the idea of "sexual embodiment" to emphasize the agency of trans women as they conceptualize and organize their sexuality in a socially recognized way. This is often difficult as they confront discrimination from medical and legal professionals as well as intimate partners who may find it difficult to adapt to the trans woman's atypical body and conception of gender. However, with a study group of 25 trans women from San Francisco, we found the study participants to be adept at overcoming such hurdles and developing techniques to "do" their sexuality. At the same time, we found trans women's agency constrained by the erotic habitus (Green, 2008) of the wider society. The interplay between innovation and cultural tradition provides an opportunity to fashion a more general model of "doing" sexuality.


Assuntos
Comportamento Sexual/psicologia , Sexualidade/psicologia , Transexualismo/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , São Francisco , Parceiros Sexuais , Adulto Jovem
9.
Regul Toxicol Pharmacol ; 73(1): 116-25, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26103602

RESUMO

Adjuvants Systems (AS) containing immunostimulant combinations are used in human vaccines. Safety pharmacology studies evaluated the cardiorespiratory effects of AS in conscious telemetered dogs and in anaesthetised rats. Sixteen telemetered beagle dogs (4/group) received intramuscular injections of saline at Day 0, and one clinical dose of AS01, AS03, AS04 or AS15 at Day 7 (7× the equivalent human dose on a bodyweight basis). Bodyweights were measured through Day 14 and cardiorespiratory parameters and body temperature through 72 h post-treatment. Anaesthetised rats (4/group) received one intravenous injection of AS01, AS03 or AS15 at 1 mL/kg bodyweight (140× the equivalent human dosages), or saline. Cardiorespiratory parameters were measured for 120 min post-dose. In dogs, food consumption and mean bodyweight decreased with AS03, and mean body temperature slightly increased with AS01, AS03 and AS15, but were not considered to be adverse. Cardiovascular effects (a slight, reversible increase in mean heart rate and shortened mean RR/PR/QT-intervals) were observed with AS15. No relevant clinical effects or effects on QRS-complex/QTc-interval durations, arterial pressure or respiratory parameters were observed. In rats, there were no consistent treatment-related effects. Collectively, this suggests that AS01, AS03, AS04 and AS15 are not associated with potentially deleterious effects on ventricular repolarisation, atrio/intra-ventricular conductivities or respiratory functions.


Assuntos
Adjuvantes Imunológicos/efeitos adversos , Sistema Cardiovascular/efeitos dos fármacos , Estado de Consciência/efeitos dos fármacos , Respiração/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Cães , Frequência Cardíaca/efeitos dos fármacos , Masculino , Modelos Animais , Ratos , Ratos Wistar , Telemetria/métodos
10.
Can Fam Physician ; 58(11): 1222-4, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23152458

RESUMO

QUESTION: In the summer months I see many children with uncomplicated acute otitis externa (AOE). I am aware of the multiple ototopical preparations. Which is the best first-line agent to treat AOE, and is there a role for an oral antibiotic? ANSWER: There are no specific Canadian guidelines for the management of AOE. However, current American guidelines promote initial ototopical therapy without systemic antibiotics for uncomplicated AOE; suggest there is little difference between the various ototopical preparations; and recommend the choice of treatment be based on the specific clinical situation. In practice, this often results in prescribing an antibiotic-steroid formulation for 7 to 10 days. This ototopical treatment option is supported by a recent Cochrane review that has documented the superiority of an antibiotic-steroid combination when compared with placebo or acetic acid in providing clinical resolution of AOE.


Assuntos
Otite Externa/diagnóstico , Otite Externa/tratamento farmacológico , Doença Aguda , Administração Tópica , Aminoglicosídeos , Antibacterianos/uso terapêutico , Criança , Contraindicações , Glucocorticoides/uso terapêutico , Humanos , Guias de Prática Clínica como Assunto
11.
Can Fam Physician ; 57(11): 1283-5, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22084458

RESUMO

QUESTION: As concern about antimicrobial resistance grows, I am aware of the need to reduce unnecessary antibiotic treatment; however, in my practice I see many children with acute otitis media (AOM) and this is the most common reason I prescribe antibiotics. Most of these children are young and otherwise healthy, and I am uncertain about when to prescribe antibiotics and when to endorse "watchful waiting." Which children will benefit from antibiotic treatment? ANSWER: Current Canadian guidelines recommend all children younger than 2 years of age with otalgia due to AOM and fever greater than 39°C be considered for treatment with amoxicillin. Watchful waiting is indicated only for children older than 6 months with mild-to-moderate AOM. Recent evidence suggests young children with a definitive diagnosis of AOM will benefit from antibiotics and experience fewer treatment failures compared with placebo, regardless of the severity of otitis. These studies do not challenge watchful waiting directly, and determining which children will improve spontaneously remains an enigma.


Assuntos
Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Otite Média/tratamento farmacológico , Conduta Expectante , Canadá , Febre/etiologia , Humanos , Lactente , Otite Média/complicações , Guias de Prática Clínica como Assunto , Índice de Gravidade de Doença
12.
Arch Sex Behav ; 39(6): 1389-401, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20127507

RESUMO

Opponents and proponents of erotic representations (referred to hereafter as "pornography") have described the effects of pornography from their perspective. Little, however, has been done in the way of research to investigate these claims from the consumer's point of view. This especially has been so regarding the positive impact of such consumption on a person's sex life. Using a study group of 245 college students, we examined this question in a framework of scripting theory. We wanted to see whether viewing pornography appeared to expand sexual horizons through normalization and facilitate a willingness to explore new sexual behaviors and sexual relationships through empowerment. The data supported this viewpoint and further showed the effects to be mediated by gender and sexual preference identity. They suggested, however, that established scripts were extended rather than abandoned. We conclude with connections between our findings and the widespread viewing of pornography in contemporary society.


Assuntos
Literatura Erótica/psicologia , Poder (Psicologia) , Comportamento Sexual/psicologia , Adolescente , Feminino , Heterossexualidade/psicologia , Homossexualidade/psicologia , Humanos , Relações Interpessoais , Masculino , Fatores Sexuais , Parceiros Sexuais/psicologia , Inquéritos e Questionários , Adulto Jovem
13.
J Sex Res ; 47(4): 374-83, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19544216

RESUMO

This article extends research on transgenderism by providing a sociological study of men who are sexually interested in transwomen (MSTW; viz., genetic males who use estrogen to feminize their body but retain their penis). We conducted fieldwork in a bar catering to transwomen and the men who were sexually interested in them, and did on-the-spot interviews with the MSTW. We initially examined the nature of MSTW's sexual attraction to transwomen, followed by how this related to their sexual orientation identity. Using a sexual fields approach (Green, 2008), we first found how the ambience of the bar helped to create an erotic environment through a heightened sense of gender. Then, focusing on the theory of embodiment (Jackson & Scott, 2007), we saw how the MSTW constructed a unique sexual desire according to the sexual orientation identity they brought to the situation. Those who identified as "straight" tended to gloss that the transwoman had a penis, while the bisexually identified men were more likely to incorporate the transwoman's penis into the sexual experience.


Assuntos
Comportamento Sexual/psicologia , Desejabilidade Social , Travestismo/psicologia , Adulto , Americanos Asiáticos/psicologia , Bissexualidade , Feminino , Identidade de Gênero , Humanos , Indiana , Entrevistas como Assunto , Libido , Masculino , Pessoa de Meia-Idade , Restaurantes , População Urbana , Adulto Jovem
15.
PLoS Biol ; 4(7): e204, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16756388

RESUMO

DNA amplification is essential to most nucleic acid testing strategies, but established techniques require sophisticated equipment or complex experimental procedures, and their uptake outside specialised laboratories has been limited. Our novel approach, recombinase polymerase amplification (RPA), couples isothermal recombinase-driven primer targeting of template material with strand-displacement DNA synthesis. It achieves exponential amplification with no need for pretreatment of sample DNA. Reactions are sensitive, specific, and rapid and operate at constant low temperature. We have also developed a probe-based detection system. Key aspects of the combined RPA amplification/detection process are illustrated by a test for the pathogen methicillin-resistant Staphylococcus aureus. The technology proves to be sensitive to fewer than ten copies of genomic DNA. Furthermore, products can be detected in a simple sandwich assay, thereby establishing an instrument-free DNA testing system. This unique combination of properties is a significant advance in the development of portable and widely accessible nucleic acid-based tests.


Assuntos
Técnicas de Amplificação de Ácido Nucleico/métodos , Bacillus subtilis/genética , Sondas de DNA , Genoma Humano , Humanos , Resistência a Meticilina/genética , Dados de Sequência Molecular , Recombinases/química , Sensibilidade e Especificidade , Staphylococcus aureus/genética , Staphylococcus aureus/isolamento & purificação
16.
Mol Microbiol ; 57(4): 1101-12, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16091047

RESUMO

Dps proteins play a major role in the protection of bacterial DNA from damage by reactive oxygen species. Previous studies have implicated the extended lysine-containing N-terminal regions of Dps subunits in DNA binding, but this part of the structure has not previously been observed crystallographically. Here the structures of two Dps proteins (DpsA and DpsB) from Lactococcus lactis MG1363 reveal for the first time the presence of an N-terminal alpha helix that extends from the core of the Dps subunit. Consequently, the N-terminal helices are displayed in parallel pairs on the exterior of the dodecameric Dps assemblies. Both DpsA and DpsB bind DNA. Deletion of the DpsA N-terminal helix impaired DNA binding. The N-terminal Lys residues of Escherichia coli Dps have been implicated in DNA binding. Replacement of the lactococcal DpsA Lys residues 9, 15 and 16 by Glu did not inhibit DNA binding. However, DNA binding was inhibited by EDTA, suggesting a role for cations in DNA binding. In contrast to E. coli, Bacillus brevis and Mycobacterium smegmatis Dps:DNA complexes, in which DNA interacts with crystalline Dps phases, L. lactis DNA:Dps complexes appeared as non-crystalline aggregates of protein and DNA in electron micrographs.


Assuntos
Proteínas de Bactérias/química , Proteínas de Ligação a DNA/química , Lactococcus lactis/metabolismo , Sequência de Aminoácidos , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/ultraestrutura , Cristalografia por Raios X , DNA/química , DNA/metabolismo , DNA/ultraestrutura , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/ultraestrutura , Dados de Sequência Molecular , Fases de Leitura Aberta , Estrutura Secundária de Proteína , Soluções/química
17.
Arch Sex Behav ; 32(6): 523-35, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14574096

RESUMO

This article presents a study of 114 self-defined zoophile men who were researched primarily through the use of an on-line questionnaire. We describe how the participants acquired the identity label of zoophile, what it meant to them, and their relationships among themselves. Also examined are how they eroticized animals and how human and feral characteristics combined to form this object choice. Finally, participants' sexual profiles with animals and humans, and how the balance of animal and human desires creates different forms of zoophilia, are described.


Assuntos
Transtornos Parafílicos/psicologia , Autorrevelação , Comportamento Sexual/psicologia , Adulto , Idoso , Animais , Austrália , Europa (Continente) , Humanos , Internet , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Inquéritos e Questionários , Estados Unidos
18.
Nat Struct Biol ; 9(6): 447-52, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11992126

RESUMO

The major bifunctional aconitase of Escherichia coli (AcnB) serves as either an enzymic catalyst or a mRNA-binding post-transcriptional regulator, depending on the status of its iron sulfur cluster. AcnB represents a large, distinct group of Gram-negative bacterial aconitases that have an altered domain organization relative to mitochondrial aconitase and other aconitases. Here the 2.4 A structure of E. coli AcnB reveals a high degree of conservation at the active site despite its domain reorganization. It also reveals that the additional domain, characteristic of the AcnB subfamily, is a HEAT-like domain, implying a role in protein protein recognition. This domain packs against the remainder of the protein to form a tunnel leading to the aconitase active site, potentially for substrate channeling.


Assuntos
Aconitato Hidratase/química , Aconitato Hidratase/metabolismo , Escherichia coli/enzimologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Sítios de Ligação , Bovinos , Sequência Conservada , Cristalografia por Raios X , Modelos Moleculares , Dados de Sequência Molecular , Complexos Multienzimáticos/química , Complexos Multienzimáticos/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , RNA/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Alinhamento de Sequência , Relação Estrutura-Atividade
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