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1.
PLoS Pathog ; 19(4): e1011342, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37068076

RESUMEN

Influenza outbreaks are associated with substantial morbidity, mortality and economic burden. Next generation antivirals are needed to treat seasonal infections and prepare against zoonotic spillover of avian influenza viruses with pandemic potential. Having previously identified oral efficacy of the nucleoside analog 4'-Fluorouridine (4'-FlU, EIDD-2749) against SARS-CoV-2 and respiratory syncytial virus (RSV), we explored activity of the compound against seasonal and highly pathogenic influenza (HPAI) viruses in cell culture, human airway epithelium (HAE) models, and/or two animal models, ferrets and mice, that assess IAV transmission and lethal viral pneumonia, respectively. 4'-FlU inhibited a panel of relevant influenza A and B viruses with nanomolar to sub-micromolar potency in HAE cells. In vitro polymerase assays revealed immediate chain termination of IAV polymerase after 4'-FlU incorporation, in contrast to delayed chain termination of SARS-CoV-2 and RSV polymerase. Once-daily oral treatment of ferrets with 2 mg/kg 4'-FlU initiated 12 hours after infection rapidly stopped virus shedding and prevented transmission to untreated sentinels. Treatment of mice infected with a lethal inoculum of pandemic A/CA/07/2009 (H1N1)pdm09 (pdmCa09) with 4'-FlU alleviated pneumonia. Three doses mediated complete survival when treatment was initiated up to 60 hours after infection, indicating a broad time window for effective intervention. Therapeutic oral 4'-FlU ensured survival of animals infected with HPAI A/VN/12/2003 (H5N1) and of immunocompromised mice infected with pdmCa09. Recoverees were protected against homologous reinfection. This study defines the mechanistic foundation for high sensitivity of influenza viruses to 4'-FlU and supports 4'-FlU as developmental candidate for the treatment of seasonal and pandemic influenza.


Asunto(s)
COVID-19 , Subtipo H1N1 del Virus de la Influenza A , Subtipo H5N1 del Virus de la Influenza A , Virus de la Influenza A , Gripe Humana , Infecciones por Orthomyxoviridae , Virus Sincitial Respiratorio Humano , Humanos , Animales , Ratones , Gripe Humana/tratamiento farmacológico , Hurones , SARS-CoV-2 , Infecciones por Orthomyxoviridae/patología
2.
Proc Natl Acad Sci U S A ; 118(3)2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33431676

RESUMEN

Pathogen interactions arising during coinfection can exacerbate disease severity, for example when the immune response mounted against one pathogen negatively affects defense of another. It is also possible that host immune responses to a pathogen, shaped by historical evolutionary interactions between host and pathogen, may modify host immune defenses in ways that have repercussions for other pathogens. In this case, negative interactions between two pathogens could emerge even in the absence of concurrent infection. Parasitic worms and tuberculosis (TB) are involved in one of the most geographically extensive of pathogen interactions, and during coinfection worms can exacerbate TB disease outcomes. Here, we show that in a wild mammal natural resistance to worms affects bovine tuberculosis (BTB) severity independently of active worm infection. We found that worm-resistant individuals were more likely to die of BTB than were nonresistant individuals, and their disease progressed more quickly. Anthelmintic treatment moderated, but did not eliminate, the resistance effect, and the effects of resistance and treatment were opposite and additive, with untreated, resistant individuals experiencing the highest mortality. Furthermore, resistance and anthelmintic treatment had nonoverlapping effects on BTB pathology. The effects of resistance manifested in the lungs (the primary site of BTB infection), while the effects of treatment manifested almost entirely in the lymph nodes (the site of disseminated disease), suggesting that resistance and active worm infection affect BTB progression via distinct mechanisms. Our findings reveal that interactions between pathogens can occur as a consequence of processes arising on very different timescales.


Asunto(s)
Búfalos/inmunología , Resistencia a la Enfermedad , Hemoncosis/microbiología , Pulmón/inmunología , Ganglios Linfáticos/inmunología , Tricostrongiliasis/microbiología , Tuberculosis Bovina/microbiología , Animales , Antinematodos/farmacología , Búfalos/microbiología , Búfalos/parasitología , Bovinos , Coinfección , Progresión de la Enfermedad , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Eosinófilos/microbiología , Eosinófilos/parasitología , Heces/parasitología , Femenino , Fenbendazol/farmacología , Hemoncosis/tratamiento farmacológico , Hemoncosis/mortalidad , Hemoncosis/parasitología , Haemonchus/efectos de los fármacos , Haemonchus/genética , Haemonchus/patogenicidad , Inmunoglobulina A/sangre , Pulmón/efectos de los fármacos , Pulmón/microbiología , Pulmón/parasitología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/microbiología , Ganglios Linfáticos/parasitología , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Mastocitos/microbiología , Mastocitos/parasitología , Mycobacterium bovis/crecimiento & desarrollo , Mycobacterium bovis/patogenicidad , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Tricostrongiliasis/tratamiento farmacológico , Tricostrongiliasis/mortalidad , Tricostrongiliasis/parasitología , Trichostrongylus/efectos de los fármacos , Trichostrongylus/genética , Trichostrongylus/patogenicidad , Tuberculosis Bovina/tratamiento farmacológico , Tuberculosis Bovina/mortalidad , Tuberculosis Bovina/parasitología
3.
PLoS Pathog ; 16(4): e1008409, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32287326

RESUMEN

The continual emergence of novel influenza A strains from non-human hosts requires constant vigilance and the need for ongoing research to identify strains that may pose a human public health risk. Since 1999, canine H3 influenza A viruses (CIVs) have caused many thousands or millions of respiratory infections in dogs in the United States. While no human infections with CIVs have been reported to date, these viruses could pose a zoonotic risk. In these studies, the National Institutes of Allergy and Infectious Diseases (NIAID) Centers of Excellence for Influenza Research and Surveillance (CEIRS) network collaboratively demonstrated that CIVs replicated in some primary human cells and transmitted effectively in mammalian models. While people born after 1970 had little or no pre-existing humoral immunity against CIVs, the viruses were sensitive to existing antivirals and we identified a panel of H3 cross-reactive human monoclonal antibodies (hmAbs) that could have prophylactic and/or therapeutic value. Our data predict these CIVs posed a low risk to humans. Importantly, we showed that the CEIRS network could work together to provide basic research information important for characterizing emerging influenza viruses, although there were valuable lessons learned.


Asunto(s)
Enfermedades Transmisibles Emergentes/veterinaria , Enfermedades de los Perros/virología , Subtipo H3N2 del Virus de la Influenza A/aislamiento & purificación , Subtipo H3N8 del Virus de la Influenza A/aislamiento & purificación , Virus de la Influenza A/aislamiento & purificación , Zoonosis/virología , Animales , Enfermedades Transmisibles Emergentes/transmisión , Enfermedades Transmisibles Emergentes/virología , Enfermedades de los Perros/transmisión , Perros , Hurones , Cobayas , Humanos , Subtipo H3N2 del Virus de la Influenza A/clasificación , Subtipo H3N2 del Virus de la Influenza A/genética , Subtipo H3N8 del Virus de la Influenza A/clasificación , Subtipo H3N8 del Virus de la Influenza A/genética , Virus de la Influenza A/clasificación , Virus de la Influenza A/genética , Gripe Humana/transmisión , Gripe Humana/virología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Estados Unidos , Zoonosis/transmisión
4.
Int J Mol Sci ; 23(10)2022 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-35628523

RESUMEN

Copper is required for aerobic respiration by Mycobacterium tuberculosis and its human host, but this essential element is toxic in abundance. Copper nutritional immunity refers to host processes that modulate levels of free copper to alternately starve and intoxicate invading microbes. Bacteria engulfed by macrophages are initially contained within copper-limited phagosomes, which fuse with ATP7A vesicles that pump in toxic levels of copper. In this report, we examine how CtpB, a P-type ATPase in M. tuberculosis, aids in response to nutritional immunity. In vitro, the induced expression of ctpB in copper-replete medium inhibited mycobacterial growth, while deletion of the gene impaired growth only in copper-starved medium and within copper-limited host cells, suggesting a role for CtpB in copper acquisition or export to the copper-dependent respiration supercomplex. Unexpectedly, the absence of ctpB resulted in hypervirulence in the DBA/2 mouse infection model. As ctpB null strains exhibit diminished growth only in copper-starved conditions, reduced copper transport may have enabled the mutant to acquire a "Goldilocks" amount of the metal during transit through copper-intoxicating environments within this model system. This work reveals CtpB as a component of the M. tuberculosis toolkit to counter host nutritional immunity and underscores the importance of elucidating copper-uptake mechanisms in pathogenic mycobacteria.


Asunto(s)
Mycobacterium tuberculosis , Tuberculosis , Animales , Cobre/metabolismo , Ratones , Ratones Endogámicos DBA , Mycobacterium tuberculosis/metabolismo , Fagosomas/metabolismo , Tuberculosis/microbiología
5.
Mol Biol Evol ; 35(2): 440-450, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29165618

RESUMEN

Macrophage Receptor with COllagenous structure (MARCO) is a class A scavenger receptor that binds, phagocytoses, and modifies inflammatory responses to bacterial pathogens. Multiple candidate gene approach studies have shown that polymorphisms in MARCO are associated with susceptibility or resistance to Mycobacterium tuberculosis infection, but how these variants alter function is not known. To complement candidate gene approach studies, we previously used phylogenetic analyses to identify a residue, glutamine 452 (Q452), within the ligand-binding Scavenger Receptor Cysteine Rich domain as undergoing positive selection in humans. Herein, we show that Q452 is found in Denisovans, Neanderthals, and extant humans, but all other nonprimate, terrestrial, and aquatic mammals possess an aspartic acid (D452) residue. Further analysis of hominoid sequences of MARCO identified an additional human-specific mutation, phenylalanine 282 (F282), within the collagenous domain. We show that residue 282 is polymorphic in humans, but only 17% of individuals (rs6761637) possess the ancestral serine residue at position 282. We show that rs6761637 is in linkage disequilibrium with MARCO polymorphisms that have been previously linked to susceptibility to pulmonary tuberculosis. To assess the functional importance of sites Q452 and F282 in humans, we cloned the ancestral residues and loss-of-function mutations and investigated the role of these residues in binding and internalizing polystyrene microspheres and Escherichia coli. Herein, we show that the residues at sites 452 and 282 enhance receptor function.


Asunto(s)
Fagocitosis/genética , Receptores Inmunológicos/genética , Selección Genética , Animales , Células HEK293 , Humanos , Mutación , Receptores Inmunológicos/metabolismo
6.
J Virol ; 92(20)2018 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-30068647

RESUMEN

J paramyxovirus (JPV) was first isolated from moribund mice with hemorrhagic lung lesions in Australia in 1972. It is a paramyxovirus classified under the newly proposed genus Jeilongvirus JPV has a genome of 18,954 nucleotides, consisting of eight genes in the order 3'-N-P/V/C-M-F-SH-TM-G-L-5'. JPV causes little cytopathic effect (CPE) in tissue culture cells but severe disease in mice. The small hydrophobic (SH) protein is an integral membrane protein encoded by many paramyxoviruses, such as mumps virus (MuV) and respiratory syncytial virus (RSV). However, the function of SH has not been defined in a suitable animal model. In this work, the functions of SH of JPV, MuV, and RSV have been examined by generating recombinant JPV lacking the SH protein (rJPV-ΔSH) or replacing SH of JPV with MuV SH (rJPV-MuVSH) or RSV SH (rJPV-RSVSH). rJPV-ΔSH, rJPV-MuVSH, and rJPV-RSVSH were viable and had no growth defect in tissue culture cells. However, more tumor necrosis factor alpha (TNF-α) was produced during rJPV-ΔSH infection, confirming the role of SH in inhibiting TNF-α production. rJPV-ΔSH induced more apoptosis in tissue culture cells than rJPV, rJPV-MuVSH, and rJPV-RSVSH, suggesting that SH plays a role in blocking apoptosis. Furthermore, rJPV-ΔSH was attenuated in mice compared to rJPV, rJPV-MuVSH, and rJPV-RSVSH, indicating that the SH protein plays an essential role in virulence. The results indicate that the functions of MuV SH and RSV SH are similar to that of JPV SH even though they have no sequence homology.IMPORTANCE Paramyxoviruses are associated with many devastating diseases in animals and humans. J paramyxovirus (JPV) was isolated from moribund mice in Australia in 1972. Newly isolated viruses, such as Beilong virus (BeiPV) and Tailam virus (TlmPV), have genome structures similar to that of JPV. A new paramyxovirus genus, Jeilongvirus, which contains JPV, BeiPV, and TlmPV, has been proposed. Small hydrophobic (SH) protein is present in many paramyxoviruses. Our present study investigates the role of SH protein of JPV in pathogenesis in its natural host. Understanding the pathogenic mechanism of Jeilongvirus is important to control and prevent potential diseases that may emerge from this group of viruses.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Infecciones por Paramyxoviridae/patología , Paramyxoviridae/crecimiento & desarrollo , Proteínas Oncogénicas de Retroviridae/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factores de Virulencia/metabolismo , Animales , Línea Celular , Chlorocebus aethiops , Modelos Animales de Enfermedad , Eliminación de Gen , Prueba de Complementación Genética , Humanos , Ratones , Viabilidad Microbiana , Virus de la Parotiditis/genética , Virus de la Parotiditis/fisiología , Infecciones por Paramyxoviridae/virología , Virus Sincitiales Respiratorios/genética , Virus Sincitiales Respiratorios/fisiología , Proteínas Oncogénicas de Retroviridae/genética , Virulencia , Factores de Virulencia/genética
7.
PLoS Pathog ; 12(5): e1005622, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-27152417

RESUMEN

Respiratory syncytial virus (RSV) is the major cause of viral lower respiratory tract illness in children. In contrast to the RSV prototypic strain A2, clinical isolate RSV 2-20 induces airway mucin expression in mice, a clinically relevant phenotype dependent on the fusion (F) protein of the RSV strain. Epidermal growth factor receptor (EGFR) plays a role in airway mucin expression in other systems; therefore, we hypothesized that the RSV 2-20 F protein stimulates EGFR signaling. Infection of cells with chimeric strains RSV A2-2-20F and A2-2-20GF or over-expression of 2-20 F protein resulted in greater phosphorylation of EGFR than infection with RSV A2 or over-expression of A2 F, respectively. Chemical inhibition of EGFR signaling or knockdown of EGFR resulted in diminished infectivity of RSV A2-2-20F but not RSV A2. Over-expression of EGFR enhanced the fusion activity of 2-20 F protein in trans. EGFR co-immunoprecipitated most efficiently with RSV F proteins derived from "mucogenic" strains. RSV 2-20 F and EGFR co-localized in H292 cells, and A2-2-20GF-induced MUC5AC expression was ablated by EGFR inhibitors in these cells. Treatment of BALB/c mice with the EGFR inhibitor erlotinib significantly reduced the amount of RSV A2-2-20F-induced airway mucin expression. Our results demonstrate that RSV F interacts with EGFR in a strain-specific manner, EGFR is a co-factor for infection, and EGFR plays a role in RSV-induced mucin expression, suggesting EGFR is a potential target for RSV disease.


Asunto(s)
Receptores ErbB/metabolismo , Mucinas/biosíntesis , Infecciones por Virus Sincitial Respiratorio/metabolismo , Proteínas Virales de Fusión/metabolismo , Animales , Western Blotting , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Técnicas de Silenciamiento del Gen , Inmunoprecipitación , Ratones , Ratones Endogámicos BALB C , Reacción en Cadena en Tiempo Real de la Polimerasa , Virus Sincitial Respiratorio Humano
8.
Curr Issues Mol Biol ; 21: 63-72, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-27443861

RESUMEN

Tuberculosis (TB) is an ancient disease caused by Mycobacterium tuberculosis (Mtb). TB is one of the world's deadliest diseases, with one-third of infected individuals falling ill each year especially in many developing countries. Upon invading host cells, such as macrophages, Mtb can replicate in infected cells by arresting phagosome maturation and then potentially escaping into the cytosol. Host cells have a mechanism to control intracellular Mtb by inducing autophagy, which is an elaborate cellular process to target intracellular pathogens for degradation in infected cells. However, some factors of Mtb are involved in defense against killing by autophagy. Thus, this review highlights the recent advances in the interactions between autophagy and Mtb.


Asunto(s)
Autofagia , Interacciones Huésped-Patógeno/fisiología , Mycobacterium tuberculosis/patogenicidad , Autofagosomas/fisiología , Humanos
10.
Immunol Cell Biol ; 94(7): 646-55, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-26888252

RESUMEN

Macrophage receptor with collagenous structure (MARCO) is a class A scavenger receptor (cA-SR) that recognizes and phagocytoses a wide variety of pathogens. Most cA-SRs that contain a C-terminal scavenger receptor cysteine-rich (SRCR) domain use the proximal collagenous domain to bind ligands. In contrast, the role of the SRCR domain of MARCO in phagocytosis, adhesion and pro-inflammatory signaling is less clear. The discovery of a naturally occurring transcript variant lacking the SRCR domain, MARCOII, provided the opportunity to study the role of the SRCR domain of MARCO. We tested whether the SRCR domain is required for ligand binding, promoting downstream signaling and enhancing cellular adhesion. Unlike cells expressing full-length MARCO, ligand binding was abolished in MARCOII-expressing cells. Furthermore, co-expression of MARCO and MARCOII impaired phagocytic function, indicating that MARCOII acts as a dominant-negative variant. Unlike MARCO, expression of MARCOII did not enhance Toll-like receptor 2 (TLR2)-mediated pro-inflammatory signaling in response to bacterial stimulation. MARCO-expressing cells were more adherent and exhibited a dendritic-like phenotype, whereas MARCOII-expressing cells were less adherent and did not exhibit changes in morphology. These data suggest the SRCR domain of MARCO is the key domain in modulating ligand binding, enhancing downstream pro-inflammatory signaling and MARCO-mediated cellular adhesion.


Asunto(s)
Empalme Alternativo/genética , Receptores Inmunológicos/química , Receptores Inmunológicos/genética , Secuencia de Aminoácidos , Animales , Adhesión Celular , Forma de la Célula , Clonación Molecular , Endocitosis , Células HEK293 , Humanos , Ligandos , Receptores de Lipopolisacáridos/metabolismo , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Dominios Proteicos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Inmunológicos/metabolismo , Streptococcus pneumoniae/fisiología , Relación Estructura-Actividad , Receptor Toll-Like 2/metabolismo
11.
J Virol ; 89(1): 512-22, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25339762

RESUMEN

UNLABELLED: Human respiratory syncytial virus (RSV) lower respiratory tract infection can result in inflammation and mucus plugging of airways. RSV strain A2-line19F induces relatively high viral load and mucus in mice. The line 19 fusion (F) protein harbors five unique residues compared to the non-mucus-inducing strains A2 and Long, at positions 79, 191, 357, 371, and 557. We hypothesized that differential fusion activity is a determinant of pathogenesis. In a cell-cell fusion assay, line 19 F was more fusogenic than Long F. We changed the residues unique to line 19 F to the corresponding residues in Long F and identified residues 79 and 191 together as responsible for high fusion activity. Surprisingly, mutation of residues 357 or 357 with 371 resulted in gain of fusion activity. Thus, we generated RSV F mutants with a range of defined fusion activity and engineered these into recombinant viruses. We found a clear, positive correlation between fusion activity and early viral load in mice; however, we did not detect a correlation between viral loads and levels of airway mucin expression. The F mutant with the highest fusion activity, A2-line19F-K357T/Y371N, induced high viral loads, severe lung histopathology, and weight loss but did not induce high levels of airway mucin expression. We defined residues 79/191 as critical for line 19 F fusion activity and 357/371 as playing a role in A2-line19F mucus induction. Defining the molecular basis of the role of RSV F in pathogenesis may aid vaccine and therapeutic strategies aimed at this protein. IMPORTANCE: Human respiratory syncytial virus (RSV) is the most important lower respiratory tract pathogen of infants for which there is no vaccine. Elucidating mechanisms of RSV pathogenesis is important for rational vaccine and drug design. We defined specific amino acids in the fusion (F) protein of RSV strain line 19 critical for fusion activity and elucidated a correlation between fusion activity and viral load in mice. Further, we identified two distinct amino acids in F as contributing to the mucogenic phenotype of the A2-line19F virus. Taken together, these results illustrate a role for RSV F in virulence.


Asunto(s)
Virus Sincitial Respiratorio Humano/fisiología , Proteínas Virales de Fusión/genética , Proteínas Virales de Fusión/metabolismo , Internalización del Virus , Animales , Línea Celular , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Femenino , Histocitoquímica , Humanos , Pulmón/patología , Pulmón/virología , Ratones Endogámicos BALB C , Infecciones por Virus Sincitial Respiratorio/patología , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitial Respiratorio Humano/patogenicidad , Carga Viral , Pérdida de Peso
12.
Clin Exp Nephrol ; 20(2): 258-64, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26349434

RESUMEN

BACKGROUND: Determination of daily protein intake in the management of chronic kidney disease (CKD) requires precision. Inaccuracies in recording dietary intake occur, and estimation from total urea excretion presents hurdles owing to the difficulty of collecting whole urine for 24 h. Spot urine has been used for measuring daily sodium intake and urinary protein excretion. METHODS: In this cross-sectional study, we investigated whether urea nitrogen (UN) concentration in spot urine can be used to predict daily protein intake instead of the 24-h urine collection in 193 Japanese CKD patients (Stages G1-G5). After patient randomization into 2 datasets for the development and validation of models, bootstrapping was used to develop protein intake estimation models. RESULTS: The parameters for the candidate multivariate regression models were male gender, age, body mass index (BMI), diabetes mellitus, dyslipidemia, proteinuria, estimated glomerular filtration rate, serum albumin level, spot urinary UN and creatinine level, and spot urinary UN/creatinine levels. The final model contained BMI and spot urinary UN level. The final model was selected because of the higher correlation between the predicted and measured protein intakes r = 0.558 (95 % confidence interval 0.400, 0.683), and the smaller distribution of the difference between the measured and predicted protein intakes than those of the other models. CONCLUSION: The results suggest that UN concentration in spot urine may be used to estimate daily protein intake and that a prediction formula would be useful for nutritional control in CKD patients.


Asunto(s)
Proteínas en la Dieta/orina , Insuficiencia Renal Crónica/orina , Urea/orina , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad
13.
Clin Exp Nephrol ; 20(6): 972-981, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26781128

RESUMEN

BACKGROUND: Kidney transplantation may release the patient receiving dialysis therapy in their life style, especially in restriction of dietary intake. However, their renal functions are not enough to take daily diet without any restriction. In Japan, we have neither standard of diet intake for them, nor data to build it. METHODS: Dietary intake and its satisfaction were surveyed in 62 outpatients who received kidney transplantation in Keio University Hospital using brief-type self-administered diet history questionnaire. RESULTS: Cross-sectional research was carried out in 2013. Estimated GFR of the object was 42 ± 16 ml/min/1.73 m2. One patient was CKD G1 stage, five in G2, 17 in G3a, 24 in G3b, 14 in G4, and one in G5. Urinary protein was shown in 30 % of patients. Their daily intake was 29 ± 8 kcal/kg of energy, 1.1 ± 0.4 g/kg of protein, 9.9 ± 3.6 g of salt. Protein and salt intakes were over comparing the respective standards for CKD in Japan. The patient who have dissatisfaction for their daily diet was significantly decreased from 79 to 4 % after their kidney transplantation. Attentions to overtake were significantly reduced after kidney transplantation from 56 to 8 % for potassium, 55 to 21 % for salt, 50 to 16 % for protein, 35 to 3 % for calcium/phosphate. CONCLUSIONS: Changes in daily diet of the patients with dialysis and kidney transplantation were recognized. The patients who received kidney transplantation would take daily diet according to their renal function although they do not have specific standards.


Asunto(s)
Dieta , Trasplante de Riñón , Adulto , Anciano , Estudios Transversales , Proteínas en la Dieta/administración & dosificación , Ingestión de Energía , Femenino , Hemoglobina Glucada/análisis , Humanos , Hiperlipidemias/etiología , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Cloruro de Sodio Dietético/administración & dosificación
14.
J Virol ; 87(23): 12990-8, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24067956

RESUMEN

J paramyxovirus (JPV) was first isolated from moribund mice with hemorrhagic lung lesions in Australia in the 1970s. Recent sequencing of JPV (JPV-LW) confirms that JPV is a paramyxovirus with several unique features. However, neither JPV-LW nor a recombinant JPV based on its sequence (rJPV-LW) caused obvious illness in mice. In this work, we analyzed a different JPV isolate (JPV-BH), which behaved differently from JPV-LW; JPV-BH grew more slowly in Vero cells and had less of a cytopathic effect on tissue culture cells but caused severe disease in mice. We have determined the whole genome sequence of JPV-BH. There were several nucleotide sequence differences between JPV-BH and JPV-LW, one in the leader sequence, one in the GX gene, and three in the L gene. The high sequence identity between JPV-BH and JPV-LW suggests that JPV-BH and JPV-LW are the same virus strain but were obtained at different passages from different laboratories. To understand the roles of these nucleotide sequence differences in pathogenicity in mice, we generated a recombinant JPV-BH strain (rJPV-BH) and hybrid rJPV-BH strains with sequences from the leader sequence (rJPV-BH-Le-LW), the GX gene (rJPV-BH-GX-LW), and the L gene (rJPV-BH-L-LW) of JPV-LW and compared their pathogenicities in mice. We have found that rJPV-BH-L-LW was attenuated in mice, indicating that nucleotide sequence differences in the L gene play a critical role in pathogenesis.


Asunto(s)
Infecciones por Paramyxoviridae/veterinaria , Paramyxovirinae/metabolismo , Paramyxovirinae/patogenicidad , Enfermedades de los Roedores/virología , Proteínas Virales/metabolismo , Animales , Línea Celular , Chlorocebus aethiops , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Infecciones por Paramyxoviridae/virología , Paramyxovirinae/genética , Proteínas Virales/genética
15.
J Virol ; 87(14): 8158-68, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23678169

RESUMEN

In recent years, many mumps outbreaks have occurred in vaccinated populations worldwide. The reasons for these outbreaks are not clear. Animal models are needed to investigate the causes of outbreaks and to understand the pathogenesis of mumps virus (MuV). In this study, we have examined the infection of three animal models with an isolate of mumps virus from a recent outbreak (MuV-IA). We have found that while both ferrets and mice generated humoral and cellular immune responses to MuV-IA infection, no obvious signs of illness were observed in these animals; rhesus macaques were the most susceptible to MuV-IA infection. Infection of rhesus macaques via both intranasal and intratracheal routes with MuV-IA led to the typical clinical signs of mumps 2 weeks to 4 weeks postinfection. However, none of the infected macaques showed any fever or neurologic signs during the experimental period. Mumps viral antigen was detected in parotid glands by immunohistochemistry (IHC). Rhesus macaques represent the best animal model for the study of mumps virus pathogenesis.


Asunto(s)
Modelos Animales de Enfermedad , Macaca mulatta , Virus de la Parotiditis/patogenicidad , Paperas/inmunología , Paperas/fisiopatología , Animales , Chlorocebus aethiops , Ensayo de Inmunoadsorción Enzimática , Hurones , Inmunohistoquímica , Ratones , Ratones Endogámicos BALB C , Paperas/virología , Pruebas de Neutralización , Glándula Parótida/virología , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Especificidad de la Especie , Células Vero
16.
J Virol ; 87(18): 10070-82, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23843644

RESUMEN

Respiratory syncytial virus (RSV) is the leading cause of death due to a viral etiology in infants. RSV disease is characterized by epithelial desquamation, neutrophilic bronchiolitis and pneumonia, and obstructive pulmonary mucus. It has been shown that infection of BALB/cJ mice with RSV clinical isolate A2001/2-20 (2-20) results in a higher early viral load, greater airway necrosis, and higher levels of interleukin-13 (IL-13) and airway mucin expression than infection with RSV laboratory strain A2. We hypothesized that the fusion (F) protein of RSV 2-20 is a mucus-inducing viral factor. In vitro, the fusion activity of 2-20 F but not that of A2 F was enhanced by expression of RSV G. We generated a recombinant F-chimeric RSV by replacing the F gene of A2 with the F gene of 2-20, generating A2-2-20F. Similar to the results obtained with the parent 2-20 strain, infection of BALB/cJ mice with A2-2-20F resulted in a higher early viral load and higher levels of subsequent pulmonary mucin expression than infection with the A2 strain. A2-2-20F infection induced greater necrotic airway damage and neutrophil infiltration than A2 infection. We hypothesized that the neutrophil response to A2-2-20F infection is involved in mucin expression. Antibody-mediated depletion of neutrophils in RSV-infected mice resulted in lower tumor necrosis factor alpha levels, fewer IL-13-expressing CD4 T cells, and less airway mucin production in the lung. Our data are consistent with a model in which the F and attachment (G) glycoprotein functional interaction leads to enhanced fusion and F is a key factor in airway epithelium infection, pathogenesis, and subsequent airway mucin expression.


Asunto(s)
Mucinas/metabolismo , Neutrófilos/inmunología , Virus Sincitiales Respiratorios/inmunología , Virus Sincitiales Respiratorios/patogenicidad , Proteínas Virales de Fusión/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Lactante , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Infecciones por Virus Sincitial Respiratorio/inmunología , Infecciones por Virus Sincitial Respiratorio/patología , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitiales Respiratorios/aislamiento & purificación , Proteínas del Envoltorio Viral/metabolismo , Proteínas Virales de Fusión/inmunología , Carga Viral
17.
Vet Radiol Ultrasound ; 55(3): 272-7, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24417646

RESUMEN

The halo sign (HS) and reverse halo sign (RHS) are radiologic signs identified on pulmonary computed tomography (CT) in people. The HS is described as a circular area of ground-glass attenuation surrounding a pulmonary nodule or mass. The RHS is defined as a focal, rounded area of ground-glass attenuation surrounded by a more or less complete ring of consolidation. These signs have been identified in a variety of diseases in people. The purpose of this retrospective study was to determine if the HS and RHS occur in dogs with pulmonary disease and to determine if they are associated with a particular disease process. In addition, the appearance of the HS and RHS was correlated with the histopathologic changes. Our results indicate that the HS and RHS are not common signs identified in dogs with pulmonary disease with an HS noted in five cases and an RHS in 4 of the 33 dogs that met the inclusion criteria. An association between the HS (P-value 0.8163) or RHS (P-value 0.5988) and neoplasia, infectious/inflammatory, and other disease processes was not identified using a Fisher's exact test. The HS was identified in neoplastic, infectious, and inflammatory conditions, with the RHS identified in neoplastic and infectious diseases and a lung lobe torsion. Histologically, the HS and RHS were caused by tumor extension, necrosis, and/or hemorrhage of the pulmonary parenchyma.


Asunto(s)
Enfermedades de los Perros/diagnóstico por imagen , Enfermedades Pulmonares/veterinaria , Pulmón/diagnóstico por imagen , Tomografía Computarizada por Rayos X/veterinaria , Animales , Perros , Georgia , Enfermedades Pulmonares/diagnóstico por imagen , Estudios Retrospectivos
18.
Cureus ; 16(6): e62274, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-39006655

RESUMEN

Endometrial carcinoma is the sixth most common cancer among women worldwide. Minimally invasive surgery (MIS) has become the preferred treatment, offering similar survival outcomes to laparotomy with lower complication rates. Corded and hyalinized endometrioid carcinoma (CHEC) is a rare and diagnostically challenging variant of endometrioid carcinoma, first described in 2005, characterized by a biphasic appearance of traditional low-grade endometrioid adenocarcinoma and corded and spindled cells embedded in a hyaline stroma. A 55-year-old nulligravid woman presented with abnormal genital bleeding for 10 days. Initial evaluations, including transvaginal ultrasonography and histological examination, confirmed adenocarcinoma. Imaging studies (magnetic resonance imaging [MRI] and computed tomography [CT]) revealed a thickened endometrium (11 mm) with no myometrial invasion, enlarged pelvic lymph nodes, or distant metastasis. Tumor markers were within normal ranges. She underwent robot-assisted laparoscopic total hysterectomy, bilateral adnexectomy, and pelvic lymph node biopsy using the da Vinci Xi system (Intuitive Surgical, Sunnyvale, CA). Histopathological examination revealed CHEC, with characteristic epithelioid and spindled cells arranged in cords within a hyalinized stroma. Immunohistochemical staining showed focal positivity for cytokeratin AE1/AE3, weak estrogen receptor positivity, and nuclear ß-catenin expression, distinguishing it from carcinosarcoma. The diagnosis was confirmed as CHEC, FIGO 2008 stage IA (pT1aN0M0). The patient remained disease-free 18 months post-surgery. CHEC is a rare variant of endometrioid carcinoma with unique histological features. It typically presents in younger patients at an early stage and has a favorable prognosis. Accurate diagnosis is crucial to differentiate it from more aggressive tumors like carcinosarcoma, preventing overtreatment. The immunohistochemical profile, particularly nuclear ß-catenin accumulation, is useful in distinguishing CHEC from carcinosarcoma. This is the first documented case of CHEC successfully treated with robot-assisted surgery. Increased awareness among pathologists and clinicians is essential for accurate diagnosis and optimal management of this rare tumor variant.

19.
bioRxiv ; 2024 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-37790571

RESUMEN

Susceptibility to respiratory virus infections (RVIs) varies widely across individuals. Because the gut microbiome impacts immune function, we investigated the influence of intestinal microbiota composition on RVI and determined that segmented filamentous bacteria (SFB), naturally acquired or exogenously administered, protected mice against influenza virus (IAV) infection. Such protection, which also applied to respiratory syncytial virus and SARS-CoV-2, was independent of interferon and adaptive immunity but required basally resident alveolar macrophages (AM). In SFB-negative mice, AM were quickly depleted as RVI progressed. In contrast, AM from SFB-colonized mice were intrinsically altered to resist IAV-induced depletion and inflammatory signaling. Yet, AM from SFB-colonized mice were not quiescent. Rather, they directly disabled IAV via enhanced complement production and phagocytosis. Accordingly, transfer of SFB-transformed AM into SFB-free hosts recapitulated SFB-mediated protection against IAV. These findings uncover complex interactions that mechanistically link the intestinal microbiota with AM functionality and RVI severity. One sentence summary: Intestinal segmented filamentous bacteria reprogram alveolar macrophages promoting nonphlogistic defense against respiratory viruses.

20.
Cell Host Microbe ; 32(3): 335-348.e8, 2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38295788

RESUMEN

Susceptibility to respiratory virus infections (RVIs) varies widely across individuals. Because the gut microbiome impacts immune function, we investigated the influence of intestinal microbiota composition on RVI and determined that segmented filamentous bacteria (SFB), naturally acquired or exogenously administered, protected mice against influenza virus (IAV) infection. Such protection, which also applied to respiratory syncytial virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was independent of interferon and adaptive immunity but required basally resident alveolar macrophages (AMs). In SFB-negative mice, AMs were quickly depleted as RVI progressed. In contrast, AMs from SFB-colonized mice were intrinsically altered to resist IAV-induced depletion and inflammatory signaling. Yet, AMs from SFB-colonized mice were not quiescent. Rather, they directly disabled IAV via enhanced complement production and phagocytosis. Accordingly, transfer of SFB-transformed AMs into SFB-free hosts recapitulated SFB-mediated protection against IAV. These findings uncover complex interactions that mechanistically link the intestinal microbiota with AM functionality and RVI severity.


Asunto(s)
Microbioma Gastrointestinal , Virosis , Animales , Ratones , Macrófagos Alveolares , Fagocitosis , Interferones , Bacterias
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