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1.
Blood ; 142(24): 2092-2104, 2023 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-37699247

RESUMO

Viral hemorrhagic fevers (HF) are a group of acute febrile diseases with high mortality rates. Although hemostatic dysfunction appears to be a major determinant of the severity of the disease, it is still unclear what pathogenic mechanisms lead to it. In clinical studies it is found that arenaviruses, such as Lassa, Machupo, and Guanarito viruses cause HF that vary in symptoms and biological alterations. In this study we aimed to characterize the hemostatic dysfunction induced by arenaviral HF to determine its implication in the severity of the disease and to elucidate the origin of this syndrome. We found that lethal infection with Machupo, Guanarito, and Lassa viruses is associated with cutaneomucosal, cerebral, digestive, and pulmonary hemorrhages. The affected animals developed a severe alteration of the coagulation system, which was concomitant with acute hepatitis, minor deficit of hepatic factor synthesis, presence of a plasmatic inhibitor of coagulation, and dysfunction of the fibrinolytic system. Despite signs of increased vascular permeability, endothelial cell infection was not a determinant factor of the hemorrhagic syndrome. There were also alterations of the primary hemostasis during lethal infection, with moderate to severe thrombocytopenia and platelet dysfunction. Finally, we show that lethal infection is accompanied by a reduced hematopoietic potential of the bone marrow. This study provides an unprecedented characterization of the hemostasis defects induced by several highly pathogenic arenaviruses.


Assuntos
Arenaviridae , Arenavirus , Febres Hemorrágicas Virais , Hemostáticos , Animais , Febres Hemorrágicas Virais/patologia , Hemorragia/etiologia , Hemostasia , Macaca
2.
Front Endocrinol (Lausanne) ; 13: 921073, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36465661

RESUMO

The common cellular origin between bone marrow adipocytes (BMAds) and osteoblasts contributes to the intimate link between bone marrow adipose tissue (BMAT) and skeletal health. An imbalance between the differentiation ability of BMSCs towards one of the two lineages occurs in conditions like aging or osteoporosis, where bone mass is decreased. Recently, we showed that the sodium-phosphate co-transporter PiT2/SLC20A2 is an important determinant for bone mineralization, strength and quality. Since bone mass is reduced in homozygous mutant mice, we investigated in this study whether the BMAT was also affected in PiT2-/- mice by assessing the effect of the absence of PiT2 on BMAT volume between 3 and 16 weeks, as well as in an ovariectomy-induced bone loss model. Here we show that the absence of PiT2 in juveniles leads to an increase in the BMAT that does not originate from an increased adipogenic differentiation of bone marrow stromal cells. We show that although PiT2-/- mice have higher BMAT volume than control PiT2+/+ mice at 3 weeks of age, BMAT volume do not increase from 3 to 16 weeks of age, leading to a lower BMAT volume in 16-week-old PiT2-/- compared to PiT2+/+ mice. In contrast, the absence of PiT2 does not prevent the increase in BMAT volume in a model of ovariectomy-induced bone loss. Our data identify SLC20a2/PiT2 as a novel gene essential for the maintenance of the BMAd pool in adult mice, involving mechanisms of action that remain to be elucidated, but which appear to be independent of the balance between osteoblastic and adipogenic differentiation of BMSCs.


Assuntos
Doenças Ósseas Metabólicas , Osteoporose , Feminino , Camundongos , Animais , Medula Óssea , Tecido Adiposo , Osteoporose/genética , Densidade Óssea
3.
Commun Biol ; 4(1): 27, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33398113

RESUMO

Lassa virus (LASV) is endemic in West Africa and induces a viral hemorrhagic fever (VHF) with up to 30% lethality among clinical cases. The mechanisms involved in control of Lassa fever or, in contrast, the ensuing catastrophic illness and death are poorly understood. We used the cynomolgus monkey model to reproduce the human disease with asymptomatic to mild or fatal disease. After initial replication at the inoculation site, LASV reached the secondary lymphoid organs. LASV did not spread further in nonfatal disease and was rapidly controlled by balanced innate and T-cell responses. Systemic viral dissemination occurred during severe disease. Massive replication, a cytokine/chemokine storm, defective T-cell responses, and multiorgan failure were observed. Clinical, biological, immunological, and transcriptomic parameters resembled those observed during septic-shock syndrome, suggesting that similar pathogenesis is induced during Lassa fever. The outcome appears to be determined early, as differentially expressed genes in PBMCs were associated with fatal and non-fatal Lassa fever outcome very early after infection. These results provide a full characterization and important insights into Lassa fever pathogenesis and could help to develop early diagnostic tools.


Assuntos
Modelos Animais de Doenças , Febre Lassa/imunologia , Febre Lassa/virologia , Macaca fascicularis , Imunidade Adaptativa , Animais , Biomarcadores/metabolismo , Feminino , Imunidade Inata , Febre Lassa/sangue , Febre Lassa/patologia , Pulmão/patologia , Tecido Linfoide/patologia , Masculino , Transcriptoma
4.
Antiviral Res ; 177: 104758, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32135218

RESUMO

BACKGROUND: In spite of recurrent and dramatic outbreaks, there are no therapeutics approved against Ebola virus disease. Favipiravir, a RNA polymerase inhibitor active against several RNA viruses, recently demonstrated significant but not complete protection in a non-human primate model of Ebola virus disease. In this study, we assessed the benefit of the combination of favipiravir and ribavirin, another broad spectrum antiviral agent, in the same model. METHODS: 15 female cynomolgus macaques were challenged intramuscularly with 1,000 FFU of Ebola virus Gabon 2001 strain and followed for 21 days. All animals received favipiravir 180 mg/kg twice a day (BID), either as monotherapy (n = 5) or in combination with ribavirin (n = 10). Ribavirin was given either at the dose 10 mg/kg BID (n = 5) or 5 mg/kg BID (n = 5). Favipiravir and ribavirin were initiated two and one days before viral challenge respectively and treatment were continued for 14 days. Treatment effects on viral and hematological markers were assessed using a mathematical model. Survival rate of 0% and 20% were obtained in macaques receiving favipiravir plus ribavirin 10 and 5 mg/kg BID, respectively, compared to 40% in the favipiravir monotherapy group (P = 0.061 when comparing monotherapy and bitherapy, log rank). Viral dynamic modeling analysis did not identify an association between plasma concentrations of ribavirin and viral load levels. Using a model of erythropoiesis, plasma concentrations of ribavirin were strongly associated with a hemoglobin drop (p = 0.0015). CONCLUSION: Ribavirin plus favipiravir did not extend survival rates and did not lower viral replication rate compared to favipiravir monotherapy in this animal model. Patients receiving this combination in other indications, such as Lassa fever, should be closely monitored to prevent potential toxicity associated with anemia.


Assuntos
Amidas/uso terapêutico , Antivirais/uso terapêutico , Ebolavirus/efeitos dos fármacos , Doença pelo Vírus Ebola/tratamento farmacológico , Pirazinas/uso terapêutico , Ribavirina/uso terapêutico , Animais , Modelos Animais de Doenças , Ebolavirus/fisiologia , Feminino , Macaca fascicularis , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
5.
Eur Spine J ; 29(10): 2534-2542, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31637549

RESUMO

PURPOSE: To describe a classification of fractures of the coccyx, according to their mechanism. METHODS: A series of 104 consecutive patients with a fracture of the coccyx was studied. The mechanism, level, characteristics of the fracture line and complications were recorded. RESULTS: Three mechanisms are proposed to describe these fractures: flexion, compression and extension (types 1, 2 and 3, respectively). Flexion fractures (38 cases) involved the upper coccyx in 35 cases, and in 3 cases with a perineal trauma, it was the lower coccyx; compression fractures (24 cases) involved the middle coccyx and occurred only when Co2 was square or cuneiform and Co3 was long and straight, hence a nutcracker mechanism; four patients were adolescents with a compression of the sacrum extremity and were labeled adolescent compression fracture of S5 (type 2b); extension fractures (38 cases) were obstetrical and involved the lower coccyx; their key feature was a progressive separation of the fragments with time. Flexion fractures usually healed spontaneously, but an associated intermittent luxation was possible. Nutcracker and obstetrical fractures were instable in their majority. CONCLUSIONS: For the first time, a classification of fractures of the coccyx is presented. Each type exhibits specific features. This should help the clinician in the management of these patients. These slides can be retrieved under Electronic Supplementary Material.


Assuntos
Fraturas por Compressão , Luxações Articulares , Fraturas da Coluna Vertebral , Adolescente , Cóccix/diagnóstico por imagem , Humanos
6.
Nat Commun ; 9(1): 4013, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30275474

RESUMO

Despite several clinical trials implemented, no antiviral drug could demonstrate efficacy against Ebola virus. In non-human primates, early initiation of polymerase inhibitors favipiravir and remdesivir improves survival, but whether they could be effective in patients is unknown. Here we analyze the impact of antiviral therapy by using a mathematical model that integrates virological and immunological data of 44 cynomolgus macaques, left untreated or treated with favipiravir. We estimate that favipiravir has a ~50% efficacy in blocking viral production, which results in reducing virus growth and cytokine storm while IFNα reduces cell susceptibility to infection. Simulating the effect of delayed initiations of treatment, our model predicts survival rates of 60% for favipiravir and 100% for remdesivir when treatment is initiated within 3 and 4 days post infection, respectively. These results improve the understanding of Ebola immuno-pathogenesis and can help optimize antiviral evaluation in future outbreaks.


Assuntos
Antivirais/uso terapêutico , Ebolavirus/imunologia , Ebolavirus/patogenicidade , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/imunologia , Interações Hospedeiro-Patógeno/imunologia , Amidas/farmacologia , Amidas/uso terapêutico , Animais , Antivirais/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Ebolavirus/efeitos dos fármacos , Feminino , Doença pelo Vírus Ebola/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , Macaca , Modelos Teóricos , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Análise de Sobrevida , Fatores de Tempo , Carga Viral/efeitos dos fármacos , Carga Viral/imunologia
7.
Viruses ; 10(9)2018 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-30227598

RESUMO

In 2009, the co-circulation of H5N1 and H1N1pdm09 raised concerns that a reassortment event may lead to highly pathogenic influenza strains. H1N1pdm09 and H5N1 are able to infect the same target cells of the lower respiratory tract. To investigate the capacity of the emergence of reassortant viruses, we characterized viruses obtained from the co-infection of cells with H5N1 (A/Turkey/13/2006) and H1N1pdm09 (A/Lyon/969/2009 H1N1). In our analysis, all the screened reassortants possessed the PB2, HA, and NP segments from H5N1 and acquired one or two of the H1N1pdm09 segments. Moreover, the in vivo infections showed that the acquisition of the NS segment from H1N1pdm09 increased the virulence of H5N1 in mice. We conclude, therefore, that reassortment can occur between these two viruses, even if this process has never been detected in nature.


Assuntos
Vírus da Influenza A Subtipo H1N1/fisiologia , Virus da Influenza A Subtipo H5N1/fisiologia , Infecções por Orthomyxoviridae/virologia , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Animais , Linhagem Celular , Coinfecção , Modelos Animais de Doenças , Genoma Viral , Camundongos , Morbidade , RNA Viral , Vírus Reordenados , Carga Viral , Virulência , Fatores de Virulência , Replicação Viral
8.
PLoS Med ; 15(3): e1002535, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29584730

RESUMO

BACKGROUND: Despite repeated outbreaks, in particular the devastating 2014-2016 epidemic, there is no effective treatment validated for patients with Ebola virus disease (EVD). Among the drug candidates is the broad-spectrum polymerase inhibitor favipiravir, which showed a good tolerance profile in patients with EVD (JIKI trial) but did not demonstrate a strong antiviral efficacy. In order to gain new insights into the antiviral efficacy of favipiravir and improve preparedness and public health management of future outbreaks, we assess the efficacy achieved by ascending doses of favipiravir in Ebola-virus-infected nonhuman primates (NHPs). METHODS AND FINDINGS: A total of 26 animals (Macaca fascicularis) were challenged intramuscularly at day 0 with 1,000 focus-forming units of Ebola virus Gabon 2001 strain and followed for 21 days (study termination). This included 13 animals left untreated and 13 treated with doses of 100, 150, and 180 mg/kg (N = 3, 5, and 5, respectively) favipiravir administered intravenously twice a day for 14 days, starting 2 days before infection. All animals left untreated or treated with 100 mg/kg died within 10 days post-infection, while animals receiving 150 and 180 mg/kg had extended survival (P < 0.001 and 0.001, respectively, compared to untreated animals), leading to a survival rate of 40% (2/5) and 60% (3/5), respectively, at day 21. Favipiravir inhibited viral replication (molecular and infectious viral loads) in a drug-concentration-dependent manner (P values < 0.001), and genomic deep sequencing analyses showed an increase in virus mutagenesis over time. These results allowed us to identify that plasma trough favipiravir concentrations greater than 70-80 µg/ml were associated with reduced viral loads, lower virus infectivity, and extended survival. These levels are higher than those found in the JIKI trial, where patients had median trough drug concentrations equal to 46 and 26 µg/ml at day 2 and day 4 post-treatment, respectively, and suggest that the dosing regimen in the JIKI trial was suboptimal. The environment of a biosafety level 4 laboratory introduces a number of limitations, in particular the difficulty of conducting blind studies and performing detailed pharmacological assessments. Further, the extrapolation of the results to patients with EVD is limited by the fact that the model is fully lethal and that treatment initiation in patients with EVD is most often initiated several days after infection, when symptoms and high levels of viral replication are already present. CONCLUSIONS: Our results suggest that favipiravir may be an effective antiviral drug against Ebola virus that relies on RNA chain termination and possibly error catastrophe. These results, together with previous data collected on tolerance and pharmacokinetics in both NHPs and humans, support a potential role for high doses of favipiravir for future human interventions.


Assuntos
Amidas/farmacologia , Amidas/farmacocinética , Antivirais/farmacologia , Ebolavirus , Doença pelo Vírus Ebola/tratamento farmacológico , Pirazinas/farmacologia , Pirazinas/farmacocinética , Animais , Relação Dose-Resposta a Droga , Feminino , Genoma Viral , Humanos , Macaca fascicularis , Mutagênese , RNA/análise , Fatores de Tempo , Pesquisa Translacional Biomédica , Carga Viral
10.
Sci Rep ; 7(1): 4099, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28642489

RESUMO

Despite sporadic outbreaks of Ebola virus (EBOV) over the last 4 decades and the recent public health emergency in West Africa, there are still no approved vaccines or therapeutics for the treatment of acute EBOV disease (EVD). In response to the 2014 outbreak, an ovine immunoglobulin therapy was developed, termed EBOTAb. After promising results in the guinea pig model of EBOV infection, EBOTAb was tested in the cynomolgus macaque non-human primate model of lethal EBOV infection. To ensure stringent therapeutic testing conditions to replicate likely clinical usage, EBOTAb was first delivered 1, 2 or 3 days post-challenge with a lethal dose of EBOV. Results showed a protective effect of EBOTAb given post-exposurally, with survival rates decreasing with increasing time after challenge. Viremia results demonstrated that EBOTAb resulted in a decreased circulation of EBOV in the bloodstream. Additionally, assay of liver enzymes and histology analysis of local tissues identified differences between EBOTAb-treated and untreated groups. The results presented demonstrate that EBOTAb conferred protection against EBOV when given post-exposure and should be explored and developed further as a potential intervention strategy for future outbreaks, which are likely to occur.


Assuntos
Anticorpos Antivirais/farmacologia , Ebolavirus/imunologia , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/imunologia , Imunoglobulina G/farmacologia , Animais , Biomarcadores , Modelos Animais de Doenças , Ebolavirus/genética , Doença pelo Vírus Ebola/mortalidade , Doença pelo Vírus Ebola/virologia , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Macaca fascicularis , Masculino , Profilaxia Pós-Exposição , Primatas , RNA Viral , Fatores de Tempo , Resultado do Tratamento , Carga Viral
11.
PLoS Negl Trop Dis ; 11(2): e0005389, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28231247

RESUMO

BACKGROUND: In 2014-2015, we assessed favipiravir tolerance and efficacy in patients with Ebola virus (EBOV) disease (EVD) in Guinea (JIKI trial). Because the drug had never been used before for this indication and that high concentrations of the drugs were needed to achieve antiviral efficacy against EBOV, a pharmacokinetic model had been used to propose relevant dosing regimen. Here we report the favipiravir plasma concentrations that were achieved in participants in the JIKI trial and put them in perspective with the model-based targeted concentrations. METHODS AND FINDINGS: Pre-dose drug concentrations were collected at Day-2 and Day-4 of treatment in 66 patients of the JIKI trial and compared to those predicted by the model taking into account patient's individual characteristics. At Day-2, the observed concentrations were slightly lower than the model predictions adjusted for patient's characteristics (median value of 46.1 versus 54.3 µg/mL for observed and predicted concentrations, respectively, p = 0.012). However, the concentrations dropped at Day-4, which was not anticipated by the model (median values of 25.9 and 64.4 µg/mL for observed and predicted concentrations, respectively, p<10-6). There was no significant relationship between favipiravir concentrations and EBOV viral kinetics or mortality. CONCLUSIONS: Favipiravir plasma concentrations in the JIKI trial failed to achieve the target exposure defined before the trial. Furthermore, the drug concentration experienced an unanticipated drop between Day-2 and Day-4. The origin of this drop could be due to severe sepsis conditions and/or to intrinsic properties of favipiravir metabolism. Dose-ranging studies should be performed in healthy volunteers to assess the concentrations and the tolerance that could be achieved with high doses. TRIAL REGISTRATION: ClinicalTrials.gov NCT02329054.


Assuntos
Amidas/farmacocinética , Antivirais/farmacocinética , Doença pelo Vírus Ebola/tratamento farmacológico , Pirazinas/farmacocinética , Adolescente , Adulto , Idoso , Amidas/administração & dosagem , Antivirais/administração & dosagem , Criança , Pré-Escolar , Ebolavirus/efeitos dos fármacos , Ebolavirus/fisiologia , Feminino , Guiné , Doença pelo Vírus Ebola/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Pirazinas/administração & dosagem , Adulto Jovem
12.
Antiviral Res ; 140: 95-105, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28132865

RESUMO

Ebola virus (EBOV) haemorrhagic fever remains a threat to global public health with an urgent need for an effective treatment. In order to achieve these goals, access to non-human primate (NHP) laboratory models is an essential requirement. Here, we present the first NHP-EBOV laboratory model readily available to the European scientific community, based on infection of Mauritian cynomolgus macaques using a Central-African EBOV strain and increasing virus challenge dose (10, 100, or 1000 focus forming units per animal). The outcome of these experiments was assessed using clinical, hematological, and biochemical criteria. All challenge doses resulted in fatal infections within 8-11 days. Symptoms appeared from day 5 after infection onwards and disease progression was slower than in previous reports based on Asian cynomolgus macaques. Thus, our model resembled human disease more closely than previous models (onset of symptoms estimated 2-21 days after infection) extending the period of time available for therapeutic intervention. To establish the dynamics of virus genome variation, the study included the first detailed analysis of major and minor genomic EBOV variants during the course of the disease. Major variants were scarce and the population of minor variants was shaped by selective pressure similar to genomic mutations observed in Nature. This primate model provides a robust baseline for future genomic studies in the context of therapeutic methods for treating Ebola virus-infected patients.


Assuntos
Ebolavirus/genética , Doença pelo Vírus Ebola/virologia , Macaca fascicularis , Animais , Modelos Animais de Doenças , Progressão da Doença , Ebolavirus/isolamento & purificação , Ebolavirus/patogenicidade , Genoma Viral , Doença pelo Vírus Ebola/terapia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
13.
Artigo em Inglês | MEDLINE | ID: mdl-27736754

RESUMO

Favipiravir is an RNA polymerase inhibitor that showed strong antiviral efficacy in vitro and in small-animal models of several viruses responsible for hemorrhagic fever (HF), including Ebola virus. The aim of this work was to characterize the complex pharmacokinetics of favipiravir in nonhuman primates (NHPs) in order to guide future efficacy studies of favipiravir in large-animal models. Four different studies were conducted in 30 uninfected cynomolgus macaques of Chinese (n = 17) or Mauritian (n = 13) origin treated with intravenous favipiravir for 7 to 14 days with maintenance doses of 60 to 180 mg/kg of body weight twice a day (BID). A pharmacokinetic model was developed to predict the plasma concentrations obtained with different dosing regimens, and the model predictions were compared to the 50% effective concentration (EC50) of favipiravir against several viruses. Favipiravir pharmacokinetics were described by a model accounting for concentration-dependent aldehyde oxidase inhibition. The enzyme-dependent elimination rate increased over time and was higher in NHPs of Mauritian origin than in those of Chinese origin. Maintenance doses of 100 and 120 mg/kg BID in Chinese and Mauritian NHPs, respectively, are predicted to achieve median trough plasma free concentrations above the EC50 for Lassa and Marburg viruses until day 7. For Ebola virus, higher doses are required. After day 7, a 20% dose increase is needed to compensate for the increase in drug clearance over time. These results will help rationalize the choice of dosing regimens in future studies evaluating the antiviral effect of favipiravir in NHPs and support its development against a variety of HF viruses.


Assuntos
Amidas/uso terapêutico , Antivirais/uso terapêutico , Febres Hemorrágicas Virais/tratamento farmacológico , Pirazinas/uso terapêutico , Administração Intravenosa , Aldeído Oxidase/metabolismo , Animais , Chlorocebus aethiops , Ebolavirus/efeitos dos fármacos , Ebolavirus/patogenicidade , Febres Hemorrágicas Virais/virologia , Primatas , Células Vero
14.
PLoS One ; 11(6): e0156775, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27280712

RESUMO

Polyclonal xenogenic IgGs, although having been used in the prevention and cure of severe infectious diseases, are highly immunogenic, which may restrict their usage in new applications such as Ebola hemorrhagic fever. IgG glycans display powerful xenogeneic antigens in humans, for example α1-3 Galactose and the glycolyl form of neuraminic acid Neu5Gc, and IgGs deprived of these key sugar epitopes may represent an advantage for passive immunotherapy. In this paper, we explored whether low immunogenicity IgGs had a protective effect on a guinea pig model of Ebola virus (EBOV) infection. For this purpose, a double knock-out pig lacking α1-3 Galactose and Neu5Gc was immunized against virus-like particles displaying surface EBOV glycoprotein GP. Following purification from serum, hyper-immune polyclonal IgGs were obtained, exhibiting an anti-EBOV GP titer of 1:100,000 and a virus neutralizing titer of 1:100. Guinea pigs were injected intramuscularly with purified IgGs on day 0 and day 3 post-EBOV infection. Compared to control animals treated with IgGs from non-immunized double KO pigs, the anti-EBOV IgGs-treated animals exhibited a significantly prolonged survival and a decreased virus load in blood on day 3. The data obtained indicated that IgGs lacking α1-3 Galactose and Neu5Gc, two highly immunogenic epitopes in humans, have a protective effect upon EBOV infection.


Assuntos
Anticorpos Antivirais/sangue , Vacinas contra Ebola/uso terapêutico , Galactose/deficiência , Doença pelo Vírus Ebola/prevenção & controle , Imunoglobulina G/imunologia , Ácidos Neuramínicos/metabolismo , Proteínas do Envelope Viral/imunologia , Animais , Anticorpos Anti-Idiotípicos/imunologia , Vacinas contra Ebola/imunologia , Ebolavirus/imunologia , Cobaias , Doença pelo Vírus Ebola/sangue , Doença pelo Vírus Ebola/imunologia , Masculino , Suínos , Vacinação , Carga Viral
15.
Eur Spine J ; 24(5): 1102-8, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25559295

RESUMO

PURPOSE: To report the results of coccygectomy for coccygeal spicule. METHODS: We report the results of a retrospective series of 33 patients who underwent coccygectomy for coccygeal spicule. There were 31 women and 2 men. The mean age was 42 ± 12 years (range 23-62). There was a pit in the skin overlying the spicule in 14 cases and the spicule was bulky in 8 cases. In three cases, weight loss had preceded the occurrence of the coccygodynia. The coccyx was rigid or had very reduced mobility (less than 5°) in 25 cases and normal mobility (between 5° and 20° of flexion) in 8 cases. All the patients had initially been managed conservatively with injections targeted on the spicule. As they did not obtain sufficient relief, they were offered surgery. Ten patients were followed up for more than 72 months, 10 patients for 48-66 months, and 13 for 30-42 months. The outcome analysis involved functional criteria only. RESULTS: Twenty-six patients (79%) had a very satisfactory outcome and 7 (21%) an unsatisfactory outcome. When asked 'Would you have the surgery again?', only one patient answered in the negative. CONCLUSIONS: Surgical treatment for coccygeal spicules that are causing coccygodynia and are resistant to conservative treatment gives satisfactory outcomes, similar to those obtained from surgery for instability of the coccyx.


Assuntos
Cóccix/cirurgia , Dor Lombar/cirurgia , Osteófito/cirurgia , Adulto , Feminino , Humanos , Dor Lombar/etiologia , Masculino , Pessoa de Meia-Idade , Medição da Dor , Satisfação do Paciente , Estudos Retrospectivos , Adulto Jovem
16.
Immunotherapy ; 6(6): 699-708, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24673720

RESUMO

AIM: There is still no specific therapy for infection with the highly pathogenic avian influenza A virus (HPAI) H5N1, which caused 39 human cases with a 64% fatality rate in 2013. MATERIALS & METHODS: We prepared highly purified specific equine polyclonal immunoglobulin fragments (F(ab')2) against H5N1 and tested them for efficacy in vitro and with different administration schedules in H5N1-challenged BALB/c mice. RESULTS: in vitro, F(ab')2 neutralized 21 different H5N1 strains from different areas, representative of 11 different clades and sub-clades and 9 years of evolution of the virus. In vivo mouse experiments identified that the most efficient administration protocol consists of five consecutive daily injections after infection; 10 mg/kg giving a 60% increase in survival. CONCLUSION: These data demonstrate the ability of anti-H5N1 F(ab')2 to markedly reduce the mortality and morbidity associated with infection of mice with HPAI H5N1 virus, and their potential for human therapy.


Assuntos
Fragmentos Fab das Imunoglobulinas/imunologia , Virus da Influenza A Subtipo H5N1/imunologia , Influenza Aviária/imunologia , Infecções por Orthomyxoviridae/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Aves , Cães , Relação Dose-Resposta a Droga , Cavalos , Humanos , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Fragmentos Fab das Imunoglobulinas/farmacologia , Virus da Influenza A Subtipo H5N1/classificação , Virus da Influenza A Subtipo H5N1/genética , Influenza Aviária/tratamento farmacológico , Influenza Aviária/mortalidade , Injeções Intraperitoneais , Células Madin Darby de Rim Canino , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/mortalidade , Filogenia , Especificidade da Espécie , Análise de Sobrevida , Taxa de Sobrevida , Fatores de Tempo
17.
Int Orthop ; 37(10): 1891-5, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23793465

RESUMO

PURPOSE: Mini invasive incisions in THA and femoral hip prostheses tend to minimise healing and recovery time. We have used a very posterior approach with technical modifications and precise skin landmarks to decrease surgical complexity, and we describe this experience here. METHODS: From 2010 to 2012, 140 patients aged 79 years (range 53-93 years) were operated upon by the same surgeon in a continuous series using the same minimally invasive skin incision and six different types of implants. The incision was very posterior in the hip allowing direct visualisation of the acetabulum in the hip flexion position and visualisation of the femoral shaft extremity in a leg flexion position. RESULTS: The mean operating time was 100 minutes (range 75-110 min). Estimated blood loss was 385 cc (20-585 cc). Twenty-six patients had blood transfusion. The mean hospital stay was 6.8 days (5-20 days) including the time waiting for a rehabilitation centre. No operative complications related to the technique were recorded. On the postoperative radiograph, the femoral stem was aligned with the femoral axis within 3° in all patients. The mean acetabular angle to the ground plane was 40° (35-48°). No patient had a leg length discrepancy of more than four millimetres. The mean skin incision length was seven centimetres (six to eight centimetres). All patients were seen at the clinic after six weeks and the data were unchanged at this time point. CONCLUSION: The method and skin landmarks we describe appear to be a safe way to perform minimally invasive total hip replacement.


Assuntos
Artroplastia de Quadril/métodos , Fraturas do Quadril/cirurgia , Articulação do Quadril/cirurgia , Prótese de Quadril , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Osteoartrite do Quadril/cirurgia , Acetábulo/cirurgia , Idoso , Idoso de 80 Anos ou mais , Feminino , Fêmur/cirurgia , Humanos , Incidência , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento
18.
Int Orthop ; 37(8): 1507-10, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23657674

RESUMO

PURPOSE: Interbody spine fusion with cages was first described by Bagby and has been performed for a long time now in a variety of different conditions. We developed a percutaneous endoscopic lumbar fusion technique based on the principles of Kambin and an original titanium cage. MATERIALS AND METHODS: From 2004 to 2010, 57 patients were operated on, 17 patients were male with a mean age of 50.29 years (range 34-71 years) and 40 were female with a mean age of 57.42 years (29-90 years). Nineteen patients had a previous operation. Patients were operated on under local anaesthesia in the prone position under image intensifier and a transforaminal percutaneous endoscopic approach. RESULTS: Fifty cases had a bilateral cage through a bilateral endoscopic approach, and seven cases had a unilateral endoscopic approach only; of those, three cases had only one cage. Eleven patients had a contemporary posterior plate fixation at the same time of the endoscopic cage fusion. Eight patients had a postoperative radicular pain with paresthesias. Asymptomatic migration of the cages occurred in two cases and symptomatic migration requiring a conventional secondary reoperation in 13 cases after a mean delay of eight months (range three to 36 months). The mean ODI after two years or more was 34.3 % (initial ODI 69.4 %). CONCLUSIONS: The technique was introduced in our practice to take care of difficult or grave co-morbidity patients, and some patients had excellent lasting results following a very short procedure and hospital stay. However, given the 36 % complication rate in this series, we do not recommend it unless decisive technical improvements are made.


Assuntos
Endoscopia/efeitos adversos , Endoscopia/métodos , Vértebras Lombares/cirurgia , Fusão Vertebral/métodos , Administração Cutânea , Adulto , Idoso , Idoso de 80 Anos ou mais , Anestesia Local , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Titânio , Resultado do Tratamento
20.
Int Orthop ; 37(7): 1291-5, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23568144

RESUMO

PURPOSE: Posterior shoulder dislocations are rare, and are usually the result of seizures. Anterior defects of the humeral head known as "reverse Hill-Sachs lesions" may increase the risk of recurrent dislocation and are difficult to treat. We developed a percutaneous technique for reduction of the dislocation or reduction of the anterior impaction fracture, using percutaneous balloon dilatation and cement fixation. METHODS: From 2009 to 2012, three patients aged 33, 72 and 75 years were admitted to our institution with a posterior shoulder dislocation showing an anterior "reverse Hill-Sachs" impaction fracture. One case was bilateral (four fractures). Patients were operated upon in the sitting position; the humeral head was stabilised by external fixator pins during balloon inflation. Reduction or filling of the defect was obtained in all cases. All patients were followed up and two patients (three fractures) were examined after one year by an independent observer. The clinical results were assessed using the Constant score and the RAND-36 physical components score. A computed tomography (CT) scan was obtained in all patients before and after the operation and at the latest follow-up. RESULTS: At three months postoperatively, all patients had resumed work or daily life activities with no limitation. The mean Constant score was 71 and RAND-36 score was 85.5. After one year, the mean Constant score was 73 and the RAND-36 score was 86.4 for the two patients who had sufficient follow-up. On the postoperative radiograph and CT scan, sphericity of the humeral head was restored, and the reverse Hill-Sachs impaction was filled or reduced in all cases. There was no recurrent dislocation. CONCLUSION: Based on this small series, we believe that this technique should be added to our current armamentarium for posterior shoulder dislocations showing a deep impaction fracture of the humeral head that are at risk for recurrent dislocation.


Assuntos
Cimentos Ósseos , Dilatação/métodos , Cabeça do Úmero/patologia , Luxação do Ombro/cirurgia , Administração Cutânea , Adulto , Idoso , Feminino , Seguimentos , Humanos , Cabeça do Úmero/diagnóstico por imagem , Masculino , Recuperação de Função Fisiológica , Luxação do Ombro/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento
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