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1.
N Engl J Med ; 384(7): 619-629, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33232588

RESUMO

BACKGROUND: Convalescent plasma is frequently administered to patients with Covid-19 and has been reported, largely on the basis of observational data, to improve clinical outcomes. Minimal data are available from adequately powered randomized, controlled trials. METHODS: We randomly assigned hospitalized adult patients with severe Covid-19 pneumonia in a 2:1 ratio to receive convalescent plasma or placebo. The primary outcome was the patient's clinical status 30 days after the intervention, as measured on a six-point ordinal scale ranging from total recovery to death. RESULTS: A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment. The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to 1:3200). No patients were lost to follow-up. At day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83; 95% confidence interval [CI], 0.52 to 1.35; P = 0.46). Overall mortality was 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of -0.46 percentage points (95% CI, -7.8 to 6.8). Total SARS-CoV-2 antibody titers tended to be higher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse events were similar in the two groups. CONCLUSIONS: No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo. (PlasmAr ClinicalTrials.gov number, NCT04383535.).


Assuntos
Anticorpos Neutralizantes/sangue , COVID-19/terapia , Imunoglobulina G/sangue , Pneumonia Viral/terapia , SARS-CoV-2/imunologia , Idoso , Idoso de 80 Anos ou mais , Transfusão de Componentes Sanguíneos , COVID-19/complicações , COVID-19/mortalidade , Progressão da Doença , Método Duplo-Cego , Feminino , Hospitalização , Humanos , Imunização Passiva , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/etiologia , Pneumonia Viral/mortalidade , Índice de Gravidade de Doença , Soroterapia para COVID-19
2.
Eur Heart J ; 44(48): 5110-5124, 2023 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-37941449

RESUMO

BACKGROUND AND AIMS: While endomyocardial biopsy (EMB) is recommended in adult patients with fulminant myocarditis, the clinical impact of its timing is still unclear. METHODS: Data were collected from 419 adult patients with clinically suspected fulminant myocarditis admitted to intensive care units across 36 tertiary centres in 15 countries worldwide. The diagnosis of myocarditis was histologically proven in 210 (50%) patients, either by EMB (n = 183, 44%) or by autopsy/explanted heart examination (n = 27, 6%), and clinically suspected cardiac magnetic resonance imaging confirmed in 96 (23%) patients. The primary outcome of survival free of heart transplantation (HTx) or left ventricular assist device (LVAD) at 1 year was specifically compared between patients with early EMB (within 2 days after intensive care unit admission, n = 103) and delayed EMB (n = 80). A propensity score-weighted analysis was done to control for confounders. RESULTS: Median age on admission was 40 (29-52) years, and 322 (77%) patients received temporary mechanical circulatory support. A total of 273 (65%) patients survived without HTx/LVAD. The primary outcome was significantly different between patients with early and delayed EMB (70% vs. 49%, P = .004). After propensity score weighting, the early EMB group still significantly differed from the delayed EMB group in terms of survival free of HTx/LVAD (63% vs. 40%, P = .021). Moreover, early EMB was independently associated with a lower rate of death or HTx/LVAD at 1 year (odds ratio of 0.44; 95% confidence interval: 0.22-0.86; P = .016). CONCLUSIONS: Endomyocardial biopsy should be broadly and promptly used in patients admitted to the intensive care unit for clinically suspected fulminant myocarditis.


Assuntos
Transplante de Coração , Miocardite , Adulto , Humanos , Miocardite/complicações , Biópsia/métodos , Cateterismo Cardíaco , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Miocárdio/patologia
3.
Int J Legal Med ; 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36066767

RESUMO

Timing bone fractures is one of the main tasks of a forensic anthropologist, but still an uncertain diagnostic. In the literature, there are many macroscopic methods to distinguish perimortem from postmortem fractures, based on the distinct structural and mechanical properties of fresh and dry bones. However, this differentiation is still challenging, in particular when the bones are fragmented or still exhibit fresh properties. Although histologic analysis is often used as a complementary diagnostic tool in forensic pathology, its application in the evaluation of bone fractures is uncommon. The aim of this study was to investigate whether fractures of fresh bones reveal a distinct microcracking pattern compared to fractures of dry bones, in order to optimise the fracture timing. To this purpose, we histologically analysed perimortem and postmortem fractures in human humeri. The fresh bones were retrieved from traumatic autopsy cases, and the dry bones from donors which were experimentally fractured. Our results showed that the highest density and length of microcracks (MCKs) were found in the interstitial area of dry fractured bones, which may be considered a marker of postmortem damage. In fresh fractured bones, we generally observed a lower density of MCKs, but a higher proportion of osteonal MCKs, which may be considered a marker of perimortem trauma. In summary, the results of our exploratory study suggest that changes in intrinsic bone factors (mineral/organic components) result in a different microcracking pattern that can be used in fracture timing.

4.
Neuroimage ; 226: 117520, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33137474

RESUMO

In the primate visual system, form (shape, location) and color information are processed in separate but interacting pathways. Recent access to high-resolution neuroimaging has facilitated the exploration of the structure of these pathways at the mesoscopic level in the human visual cortex. We used 7T fMRI to observe selective activation of the primary visual cortex to chromatic versus achromatic stimuli in five participants across two scanning sessions. Achromatic checkerboards with low spatial frequency and high temporal frequency targeted the color-insensitive magnocellular pathway. Chromatic checkerboards with higher spatial frequency and low temporal frequency targeted the color-selective parvocellular pathway. This work resulted in three main findings. First, responses driven by chromatic stimuli had a laminar profile biased towards superficial layers of V1, as compared to responses driven by achromatic stimuli. Second, we found stronger preference for chromatic stimuli in parafoveal V1 compared with peripheral V1. Finally, we found alternating, stimulus-selective bands stemming from the V1 border into V2 and V3. Similar alternating patterns have been previously found in both NHP and human extrastriate cortex. Together, our findings confirm the utility of fMRI for revealing details of mesoscopic neural architecture in human cortex.


Assuntos
Percepção de Cores/fisiologia , Córtex Visual/fisiologia , Adulto , Mapeamento Encefálico/métodos , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Reconhecimento Visual de Modelos/fisiologia , Estimulação Luminosa/métodos , Adulto Jovem
5.
Molecules ; 26(1)2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33401754

RESUMO

Using the classical Ugi four-component reaction to fuse an amine, ketone, carboxylic acid, and isocyanide, here we prepared a short library of N-alkylated α,α-dialkylglycine derivatives. Due to the polyfunctionality of the dipeptidic scaffold, this highly steric hindered system shows an interesting acidolytic cleavage of the C-terminal amide. In this regard, we studied the structure-acid lability relationship of the C-terminal amide bond (cyclohexylamide) of N-alkylated α,α-dialkylglycine amides 1a-n in acidic media and, afterward, it was established that the most important structural features related to its cleavage. Then, it was demonstrated that electron-donating effects in the aromatic amines, flexible acyl chains (Gly) at the N-terminal and the introduction of cyclic compounds into dipeptide scaffolds, increased the rate of acidolysis. All these effects are related to the ease with which the oxazolonium ion intermediate forms and they promote the proximity of the central carbonyl group to the C-terminal amide, resulting in C-terminal amide cleavage. Consequently, these findings could be applied for the design of new protecting groups, handles for solid-phase synthesis, and linkers for conjugation, due to its easily modulable and the fact that it allows to fine tune its acid-lability.


Assuntos
Dipeptídeos/química , Glicina/análogos & derivados , Glicina/química , Alquilação , Amidas/química , Aminas/química , Técnicas de Química Sintética , Cianetos/química , Hidrólise , Estrutura Molecular , Oxazinas/química , Solubilidade
6.
Int J Legal Med ; 134(5): 1765-1774, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32592073

RESUMO

Timing of cranial trauma is challenging in forensic cases and literature on the subject is scarce. This study analysed the macroscopic fracture patterns of perimortem cranial fractures and compared them to experimentally reproduced cranial fractures on dry human craniums. The results showed nine traits associated with fresh cranial fractures: undulated margin, flake defects, peels with peel defects, fissures, crushed margins, bridge, bone scales and beveling. All the traits appear on the outer table or on the inner table of the cranium. Although not all characteristics must be present at the same time in all cranial fractures, they do define a new perimortem fracture pattern. Statistical analyses showed that six of these traits (undulated margins, flake defects, crushed margins, bone scales, fissures and peels) are distinctly related with perimortem (fresh) bone conditions. Considering the most discriminant perimortem traits, a decision-making algorithm is developed as a probabilistic approach to distinguish peri- from postmortem cranial fractures with an accuracy of 87%. This algorithm allows the forensic practitioner to incorporate more confidence during cranial trauma evaluation.


Assuntos
Medicina Legal/métodos , Fraturas Cranianas/patologia , Crânio/lesões , Adulto , Idoso , Algoritmos , Árvores de Decisões , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mudanças Depois da Morte
7.
Clin Orthop Relat Res ; 478(6): 1348-1355, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32106134

RESUMO

BACKGROUND: Surgical débridement, antibiotics and implant retention (DAIR) is currently recommended by international guidelines for both early acute (postsurgical) and late acute (hematogenous) periprosthetic joint infections (PJIs). However, due to a different pathogenesis of infection, a different treatment strategy may be needed. QUESTIONS/PURPOSES: (1) Compared with early acute PJIs, are late acute PJIs associated with a higher risk of DAIR failure? (2) When stratified by microorganism, is the higher risk of failure in late acute PJI associated with Staphylocococcus aureus infection? (3) When analyzing patients with S. aureus infection, what factors are independently associated with DAIR failure? METHODS: In this multicenter observational study, early acute and late acute PJIs treated with DAIR were retrospectively evaluated and matched according to treating center, year of diagnosis, and infection-causing microorganism. If multiple matches were available, the early acute PJI diagnosed closest to the late acute PJI was selected. A total of 132 pairs were included. Treatment success was defined as a retained implant during follow-up without the need for antibiotic suppressive therapy. RESULTS: Late acute PJIs had a lower treatment success (46% [60 of 132]) compared with early acute PJIs (76% [100 of 132]), OR 3.9 [95% CI 2.3 to 6.6]; p < 0.001), but the lower treatment success of late acute PJIs was only observed when caused by Staphylococcus spp (S. aureus: 34% versus 75%; p < 0.001; coagulase-negative staphylococci: 46% versus 88%; p = 0.013, respectively). On multivariable analysis, late acute PJI was the only independent factor associated with an unsuccessful DAIR when caused by S. aureus (OR 4.52 [95% CI 1.79 to 11.41]; p < 0.001). CONCLUSIONS: Although DAIR seems to be a successful therapeutic strategy in the management of early acute PJI, its use in late acute PJI should be reconsidered when caused by Staphylococcus spp. Our results advocate the importance of isolating the causative microorganism before surgery. LEVEL OF EVIDENCE: Level III, therapeutic study.


Assuntos
Artroplastia de Substituição/efeitos adversos , Desbridamento , Prótese Articular/efeitos adversos , Retenção da Prótese , Infecções Relacionadas à Prótese/cirurgia , Infecções Estafilocócicas/cirurgia , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Artroplastia de Substituição/instrumentação , Desbridamento/efeitos adversos , Europa (Continente) , Feminino , Humanos , Masculino , Retenção da Prótese/efeitos adversos , Infecções Relacionadas à Prótese/diagnóstico , Infecções Relacionadas à Prótese/microbiologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/microbiologia , Fatores de Tempo , Falha de Tratamento
8.
Forensic Sci Med Pathol ; 16(2): 281-286, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32201926

RESUMO

Perimortem fracture patterns in long bones, defined in previous publications, include layered breakage, bone scales, crushed margins, flakes with flake defect, wave lines, and plastic deformation. The traits help professionals during trauma analysis to differentiate peri- from post-mortem fractures. This study will therefore investigate whether these traits can be recorded with Computed Tomography (CT) as the non-invasive 3D imaging technique is becoming more popular in forensic science. CT scans of macerated bone samples (n = 15; humerus: n = 1; ulna: n = 1; radius: n = 1; femur: n = 12) were investigated using multi-planar reconstructions (MPRs) and volume renderings. Tension lines and severe plastic deformation were visible on the individual multi-planar reconstructions (MPRs) and the 3D models. Additionally, layered breakage and flake defects were also clearly distinguishable on the volume renderings. Based on the results, CT imaging may be a useful and fast tool to document, visualize, and analyze findings of blunt force trauma.


Assuntos
Fraturas Ósseas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Documentação , Antropologia Forense , Humanos , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional
9.
Int J Legal Med ; 133(2): 661-668, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30377776

RESUMO

This study aims to improve a previous study that reported new traits to characterize a perimortem fracture pattern in human long bones. This second study aims to acquire further knowledge about these perimortem traits, specifically by improving the experimental setting-by using a Blunt Force Trauma Simulator-and increasing the sample size with a total of 43 autopsy specimens and 57 reproduced fractures. Additionally, we investigated whether these traits could be related to muscular contractions by adding axial compression in the experimentally fractured specimens. If intra vitam traits can be found, it would consequentially be more valuable for forensic anthropologists to shorten the perimortem period. We demonstrate that all traits are perimortem traits. Furthermore, based on our results, we see the tendency that the combination of traits-instead of the presence of each trait individually-may make it possible to distinguish intra vitam from perimortem fractures. This study confirms these distinct characteristics that can be valuable to utilize in the distinction between peri- and postmortem fractures.


Assuntos
Morte , Fraturas Ósseas/patologia , Idoso , Idoso de 80 Anos ou mais , Antropologia Forense , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Modelos Biológicos
10.
Int J Legal Med ; 132(4): 1205-1213, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29502222

RESUMO

Literature on timing of rib trauma is scarce but remains challenging during forensic cases. This study analysed the macroscopic fracture patterns of perimortem rib fractures and compared them to experimentally reproduced rib fractures on fresh and dry ribs. Six distinctive macroscopic traits were found in ribs that might provide information about the timing of trauma, fracture mechanism and/or trauma circumstances. These traits are peels, folds, differential fracture edges, incomplete fractures, plastic deformation and longitudinal lines. Peels, folds and plastic deformation might provide information about trauma timing. Folds and different fracture edges might provide information about the fracture mechanism. Statistical analyses showed that longitudinal lines, folds and incomplete fractures might provide information about the trauma circumstances and that age might have an influence on the occurrence of complete fractures, longitudinal lines and peels (p ≤ 0.05). The new insights presented in this study might be valuable for forensic anthropologists in rib trauma analysis.


Assuntos
Fraturas das Costelas/patologia , Ferimentos não Penetrantes/complicações , Acidentes , Adulto , Idoso , Idoso de 80 Anos ou mais , Reanimação Cardiopulmonar/efeitos adversos , Feminino , Patologia Legal , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Fraturas das Costelas/etiologia , Fatores de Tempo , Adulto Jovem
11.
Int J Legal Med ; 131(3): 867-875, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27942870

RESUMO

Determining the time of injury is an important but still a challenging task in forensic anthropology. In literature, many descriptions can be found to make a distinction between perimortem and postmortem fractures. Characteristics that are more related to fractures in fresh conditions, however, are not extensively investigated. This study compared 28 perimortem fractures from autopsies and 21 both fresh and dry experimentally reproduced human bone fractures. Preliminary results showed the following five distinct traits that might be related to perimortem conditions: layered breakage, bone scales, crushed margins, wave lines and flakes with matching flake defect. These distinct traits might not only be good estimators of perimortem trauma but also may be an indicator of trauma in intra vitam conditions, especially related with muscular reaction to injury. Furthermore, layered breakage seems to be a good trait to infer the biomechanics of trauma.


Assuntos
Fraturas Ósseas/patologia , Ferimentos não Penetrantes/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Fenômenos Biomecânicos , Feminino , Antropologia Forense/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto Jovem
12.
Medicina (B Aires) ; 77(2): 143-157, 2017.
Artigo em Espanhol | MEDLINE | ID: mdl-28463223

RESUMO

Surgical site infections complicating orthopedic implant surgeries prolong hospital stay and increase risk of readmission, hospitalization costs and mortality. These recommendations are aimed at: (i) optimizing compliance and incorporating habits in all surgery phases by detecting risk factors for surgical site infections which are potentially correctable or modifiable; and (ii) optimizing preoperative antibiotic prophylaxis as well as intraoperative and postoperative care.


Assuntos
Antibioticoprofilaxia/métodos , Artroplastia/efeitos adversos , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Infecção da Ferida Cirúrgica/prevenção & controle , Adulto , Humanos , Fatores de Risco
13.
J Virol ; 89(12): 6494-505, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25855749

RESUMO

UNLABELLED: Dengue virus (DENV) is a major public health threat worldwide. Infection with one of the four serotypes of DENV results in a transient period of protection against reinfection with all serotypes (cross-protection), followed by lifelong immunity to the infecting serotype. While a protective role for neutralizing antibody responses is well established, the contribution of T cells to reinfection is less clear, especially during heterotypic reinfection. This study investigates the role of T cells during homotypic and heterotypic DENV reinfection. Mice were sequentially infected with homotypic or heterotypic DENV serotypes, and T cell subsets were depleted before the second infection to assess the role of DENV-primed T cells during reinfection. Mice primed nonlethally with DENV were protected against reinfection with either a homotypic or heterotypic serotype 2 weeks later. Homotypic priming induced a robust neutralizing antibody response, whereas heterotypic priming elicited binding, but nonneutralizing antibodies. CD8(+) T cells were required for protection against heterotypic, but not homotypic, reinfection. These results suggest that T cells can contribute crucially to protection against heterotypic reinfection in situations where humoral responses alone may not be protective. Our findings have important implications for vaccine design, as they suggest that inducing both humoral and cellular responses during vaccination may maximize protective efficacy across all DENV serotypes. IMPORTANCE: Dengue virus is present in more than 120 countries in tropical and subtropical regions. Infection with dengue virus can be asymptomatic, but it can also progress into the potentially lethal severe dengue disease. There are four closely related dengue virus serotypes. Infection with one serotype results in a transient period of resistance against all serotypes (cross-protection), followed by lifelong resistance to the infecting serotype, but not the other ones. The duration and mechanisms of the transient cross-protection period remain elusive. This study investigates the contribution of cellular immunity to cross-protection using mouse models of DENV infection. Our results demonstrate that cellular immunity is crucial to mediate cross-protection against reinfection with a different serotype, but not for protection against reinfection with the same serotype. A better understanding of the mediators responsible for the cross-protection period is important for vaccine design, as an ideal vaccine against dengue virus should efficiently protect against all serotypes.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Proteção Cruzada , Vírus da Dengue/imunologia , Dengue/prevenção & controle , Animais , Modelos Animais de Doenças , Feminino , Procedimentos de Redução de Leucócitos , Masculino , Camundongos , Recidiva , Fatores de Tempo
14.
J Virol ; 89(10): 5592-601, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25762732

RESUMO

UNLABELLED: The host-targeted antiviral drug UV-4B reduces viral replication and promotes survival in a mouse model of experimental dengue virus (DENV) infection. UV-4B is an iminosugar that inhibits the α-glucosidase family of enzymes and subsequently the folding of glycosylated proteins, both viral and host. Here, we utilized next-generation sequencing to investigate evolution of a flavivirus under selective pressure by a host-targeted antiviral in vivo. In viral populations recovered from UV-4B-treated mice, there was a significant increase in the number of single-nucleotide polymorphisms (SNPs) and the ratio of nonsynonymous to synonymous SNPs compared to findings in viral populations from vehicle-treated mice. The strongest evidence of positive selection was in the glycosylated membrane protein, thereby providing in vivo validation of the mechanism of action of an iminosugar. In addition, mutations in glycosylated proteins were present only in drug-treated mice after a single passage. However, the bulk of the other mutations were present in both populations, indicating nonspecific selective pressure. Together with the continued control of viremia by UV-4B, these findings are consistent with the previously predicted high genetic barrier to escape mutations in host-targeted antivirals. IMPORTANCE: Although hundreds of millions of people are infected with DENV every year, there is currently no approved vaccine or antiviral therapy. UV-4B has demonstrated antiviral activity against DENV and is expected to enter clinical trials soon. Therefore, it is important to understand the mechanisms of DENV resistance to UV-4B. Host-targeted antivirals are thought to have a higher genetic barrier to escape mutants than directly acting antivirals, yet there are very few published studies of viral evolution under host-targeted antivirals. No study to date has described flavivirus evolution in vivo under selective pressure by a host-based antiviral drug. We present the first in vivo study of the sequential progression of viral evolution under selective pressure by a host-targeted antiviral compound. This study bolsters support for the clinical development of UV-4B as an antiviral drug against DENV, and it provides a framework to compare how treatment with other host-targeted antiflaviviral drugs in humans and different animal models influence viral genetic diversity.


Assuntos
Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Vírus da Dengue/genética , Dengue/tratamento farmacológico , Dengue/virologia , Animais , Vírus da Dengue/fisiologia , Modelos Animais de Doenças , Evolução Molecular , Variação Genética , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Imino Açúcares/farmacologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Mutação , Polimorfismo de Nucleotídeo Único , Seleção Genética , Proteínas Virais/genética , Replicação Viral/efeitos dos fármacos
16.
J Immunol ; 191(8): 4194-201, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24043884

RESUMO

We investigated the roles of IFN regulatory factor (IRF)-3 and IRF-7 in innate antiviral immunity against dengue virus (DENV). Double-deficient Irf-3(-/-)7(-/-) mice infected with the DENV2 strain S221 possessed 1,000-150,000 fold higher levels of viral RNA than wild-type and single-deficient mice 24 h postinfection (hpi); however, they remained resistant to lethal infection. IFN-α/ß was induced similarly in wild-type and Irf-3(-/-) mice post-DENV infection, whereas in the Irf-7(-/-) and Irf-3(-/-)7(-/-) mice, significantly low levels of IFN-α/ß expression was observed within 24 hpi. IFN-stimulated gene induction was also delayed in Irf-3(-/-)7(-/-) mice relative to wild-type and single-deficient mice. In particular, Cxcl10 and Ifnα2 were rapidly induced independently of both IRF-3 and IRF-7 in the Irf-3(-/-)7(-/-) mice with DENV infection. Higher levels of serum IFN-γ, IL-6, CXCL10, IL-8, IL-12 p70, and TNF were also observed in Irf-3(-/-)7(-/-) mice 24 hpi, at which time point viral titers peaked and started to be cleared. Ab-mediated blockade experiments revealed that IFN-γ, CXCL10, and CXCR3 function to restrict DENV replication in Irf-3(-/-)7(-/-) mice. Additionally, the IFN-stimulated genes Cxcl10, Ifit1, Ifit3, and Mx2 can be induced via an IRF-3- and IRF-7-independent pathway that does not involve IFN-γ signaling for protection against DENV. Collectively, these results demonstrate that IRF-3 and IRF-7 are redundant, albeit IRF-7 plays a more important role than IRF-3 in inducing the initial IFN-α/ß response; only the combined actions of IRF-3 and IRF-7 are necessary for efficient control of early DENV infection; and the late, IRF-3- and IRF-7-independent pathway contributes to anti-DENV immunity.


Assuntos
Vírus da Dengue/imunologia , Dengue/imunologia , Imunidade Inata , Fator Regulador 3 de Interferon/metabolismo , Fator Regulador 7 de Interferon/metabolismo , Interferon-alfa/sangue , Interferon beta/sangue , Proteínas Adaptadoras de Transdução de Sinal , Aedes , Animais , Proteínas de Transporte/metabolismo , Linhagem Celular , Quimiocina CXCL10/biossíntese , Quimiocina CXCL10/sangue , Quimiocina CXCL10/imunologia , Fator Regulador 3 de Interferon/deficiência , Fator Regulador 3 de Interferon/genética , Fator Regulador 7 de Interferon/deficiência , Fator Regulador 7 de Interferon/genética , Interferon gama/sangue , Interferon gama/imunologia , Interleucina-12/sangue , Interleucina-6/sangue , Interleucina-8/sangue , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Resistência a Myxovirus/metabolismo , Proteínas/metabolismo , RNA Viral/sangue , Proteínas de Ligação a RNA , Receptores CXCR3/imunologia , Transdução de Sinais , Fatores de Necrose Tumoral/sangue , Carga Viral , Replicação Viral/imunologia
18.
Rev Esp Salud Publica ; 982024 Jun 05.
Artigo em Espanhol | MEDLINE | ID: mdl-38899691

RESUMO

OBJECTIVE: Data on drownings tend to underestimate mortality from this cause. The objective of this study was to describe fatal drownings recorded in Catalonia between 2019 and 2022 through forensic sources, present their characteristics, and assess the utility of this information for monitoring drowning mortality. METHODS: A retrospective observational study based on the register of judicial deaths from the Institute of Legal Medicine and Forensic Sciences of Catalonia was carried out. Data on medicolegal aetiology, aquatic environment, age, gender, date of death, and municipality of origin were analysed. Statistical analysis was based on the comparison of proportions test based on Chi-square for categorical variables and the Mann Whitney U test for the comparison of numerical variables. RESULTS: A total of 310 drownings were recorded, with a mean age of 57.2 years and a male predominance (77.1%). The majority of drownings were unintentional (71.3%), followed by suicides (15.5%), and cases of undetermined intent (12.6%). Compared to intentional drownings, unintentional and undetermined intent drownings had a higher percentage of males than females (81.2% vs. 56%, p<0.001), and fewer cases with Spanish nationality than foreign or undetermined nationality (60% vs. 92%, p<0.001). Middle-aged and older individuals accounted for the majority of deaths, but among unintentional drownings, those recorded in pools included significantly higher percentages of children and adolescents aged zero-fourteen years than those occurring in natural waters. CONCLUSIONS: The results highlight the importance of drowning mortality in Catalonia and the need to strengthen preventive activities, especially for children and during episodes of intense heat. Medicolegal sources are useful for monitoring drowning mortality, but it would be beneficial if they incorporated information on variables such as place of residence and nationality.


OBJETIVO: Los datos sobre ahogamientos tienden a subestimar la mortalidad por esta causa. El objetivo de este estudio fue describir los ahogamientos mortales registrados en Cataluña entre 2019 y 2022 a través de fuentes forenses, mostrar sus características y valorar la utilidad de esta información para monitorizar la mortalidad por ahogamientos. METODOS: Se realizó un estudio observacional retrospectivo basado en el registro de muertes judiciales del Instituto de Medicina Legal y Ciencias Forenses de Cataluña. Se analizaron la etiología médico-legal, entorno acuático, edad, sexo, fecha de defunción y municipio de procedencia. El análisis estadístico se basó en la prueba de comparación de proporciones basada en Chi cuadrado para las variables categóricas y la prueba U de Mann Whitney para la comparación de variables numéricas. RESULTADOS: Se registraron 310 ahogamientos mortales, con una edad media de 57,2 años y predominio masculino (77,1%). La mayoría fueron no intencionales (71,3%), seguidos por suicidios (15,5%) y casos de intencionalidad indeterminada (12,6%). Comparados con los ahogamientos intencionales, los no intencionales y de intencionalidad indeterminada incluyeron más hombres que mujeres (81,2% frente a 56%, p<0,001), y menos casos con nacionalidad española que extranjera o indeterminada (60% frente a 92%, p<0,001). Las personas de mediana y avanzada edad aportaron la mayoría de las defunciones pero, entre los ahogamientos no intencionales, los registrados en piscinas incluyeron más niños y adolescentes de cero-catorce años que los que tuvieron lugar en aguas naturales. CONCLUSIONES: Los resultados prueban la importancia de los ahogamientos mortales en Cataluña y la necesidad de fortalecer las actividades preventivas, especialmente en la infancia y durante episodios de calor intenso. Las fuentes médico-forenses son útiles para monitorizar la mortalidad por ahogamientos, pero convendría que incorporaran variables como el lugar de residencia y la nacionalidad.


Assuntos
Afogamento , Humanos , Masculino , Feminino , Espanha/epidemiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Afogamento/mortalidade , Idoso , Adulto , Criança , Adolescente , Pré-Escolar , Adulto Jovem , Lactente , Idoso de 80 Anos ou mais , Recém-Nascido , Distribuição por Sexo
19.
ACR Open Rheumatol ; 6(4): 189-200, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38265177

RESUMO

OBJECTIVE: Acute visual impairment is the most feared complication of giant cell arteritis (GCA) but is challenging to predict. Magnetic resonance imaging (MRI) evaluates orbital pathology not visualized by an ophthalmologic examination. This study combined orbital and cranial vessel wall MRI to assess both orbital and cranial disease activity in patients with GCA, including patients without visual symptoms. METHODS: Patients with suspected active GCA who underwent orbital and cranial vessel wall MRI were included. In 14 patients, repeat imaging over 12 months assessed sensitivity to change. Clinical diagnosis of ocular or nonocular GCA was determined by a rheumatologist and/or ophthalmologist. A radiologist masked to clinical data scored MRI enhancement of structures. RESULTS: Sixty-four patients with suspected GCA were included: 25 (39%) received a clinical diagnosis of GCA, including 12 (19%) with ocular GCA. Orbital MRI enhancement was observed in 83% of patients with ocular GCA, 38% of patients with nonocular GCA, and 5% of patients with non-GCA. MRI had strong diagnostic performance for both any GCA and ocular GCA. Combining MRI with a funduscopic examination reached 100% sensitivity for ocular GCA. MRI enhancement significantly decreased after treatment (P < 0.01). CONCLUSION: In GCA, MRI is a sensitive tool that comprehensively evaluates multiple cranial structures, including the orbits, which are the most concerning site of pathology. Orbital enhancement in patients without visual symptoms suggests that MRI may detect at-risk subclinical ocular disease in GCA. MRI scores decreased following treatment, suggesting scores reflect inflammation. Future studies are needed to determine if MRI can identify patients at low risk for blindness who may receive less glucocorticoid therapy.

20.
Biology (Basel) ; 12(3)2023 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-36979091

RESUMO

In forensic anthropology, the differential diagnosis between peri- and postmortem bone fractures is mainly based on macroscopic criteria. In contrast, studies focusing on bone histology are very scarce. In a recent publication, we showed that (perimortem) fractures in fresh human bones exhibit a different osteonal microcracking pattern than (postmortem) damage in dry bones. In the current work, we explored whether this osteonal microcracking pattern is distinctive of the vitality of (perimortem) fresh bone fractures. To this end, we compared the number, length and structural distribution of microcracks in vital humeral fractures from forensic autopsy cases with experimentally reproduced, three point-bending fractures in fresh and dry human humeri. Half of the fresh experimental bones were fractured whilst applying axial compression, i.e., attempting to simulate intra vitam conditions more accurately. The results showed a similar osteonal microcracking pattern between vital fractures and experimental fractures of fresh humeri subjected to axial compression. Interestingly, this pattern was significantly different from the one observed in the experimental fractures of fresh humeri without axial compression and dry humeri. This supports our hypothesis that the osteonal microcracking pattern can potentially be used as a marker for vital perimortem trauma, providing a histomorphometric tool for fracture timing.

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