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Micronutrient malnutrition is widespread and is linked with diets low in fruit and vegetables. However, during the twentieth century, declines in essential minerals in fruits and vegetables were reported in the UK and elsewhere. A new analysis of long-term trends of the mineral content of fruits and vegetables from three editions of the UK's Composition of Foods Tables (1940, 1991 and 2019) was undertaken. All elements except P declined in concentrations between 1940 and 2019 - the greatest overall reductions during this 80-year period were Na (52%), Fe (50%), Cu (49%) and Mg (10%); water content increased (1%). There could be many reasons for these reductions, including changes in crop varieties and agronomic factors associated with the industrialisation of agriculture. Increases in carbon dioxide could also play a role. We call for a thorough investigation of these reductions and steps to be taken to address the causes that could contribute to global malnutrition.
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Desnutrição , Verduras , Agricultura , Dieta , Frutas , Humanos , Minerais , Reino UnidoRESUMO
BACKGROUND: People face varying obstacles when interacting with health information in their everyday lives. OBJECTIVES: This study aims to examine the applicability of a multidimensional Everyday Health Information Literacy (EHIL) screening tool in detecting people with challenges in accessing, understanding, evaluating and using health information in everyday situations. METHODS: Previously collected EHIL screening tool data from Finnish upper secondary school students (n = 217), Finnish young men (n = 1450), Finnish adults with an increased risk for metabolic syndrome (n = 559) and Namibian university students (n = 271) were reanalysed to examine the factorial structure of the tool and to compare the groups. Statistical analyses included exploratory factor analyses, calculation of mean factor scores and one-way analysis of variance. RESULTS: A three factor structure ('awareness', 'access', 'assessment') for the screening tool was supported based on the Finnish samples. However, the Namibian data did not follow a similar structure. Significant differences in groupwise factor scores were discovered. DISCUSSION: The findings suggest that the multidimensional EHIL screening tool can be used in pointing out areas where individuals or groups may need support. CONCLUSION: The tool may be useful to health information and library services workers when counselling or educating the public.
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Letramento em Saúde/normas , Programas de Rastreamento/métodos , Adolescente , Análise de Variância , Feminino , Finlândia , Humanos , Competência em Informação , Masculino , Adulto JovemRESUMO
HCM, the most common inherited cardiac disease, is mainly caused by mutations in sarcomeric genes. More than a third of the patients are heterozygous for mutations in the MYH7 gene encoding for the ß-myosin heavy chain. In HCM-patients, expression of the mutant and the wildtype allele can be unequal, thus leading to fractions of mutant and wildtype mRNA and protein which deviate from 1:1. This so-called allelic imbalance was detected in whole tissue samples but also in individual cells. There is evidence that the severity of HCM not only depends on the functional effect of the mutation itself, but also on the fraction of mutant protein in the myocardial tissue. Allelic imbalance has been shown to occur in a broad range of genes. Therefore, we aimed to examine whether the MYH7-alleles are intrinsically expressed imbalanced or whether the allelic imbalance is solely associated with the disease. We compared the expression of MYH7-alleles in non-HCM donors and in HCM-patients with different MYH7-missense mutations. In the HCM-patients, we identified imbalanced as well as equal expression of both alleles. Also at the protein level, allelic imbalance was determined. Most interestingly, we also discovered allelic imbalance and balance in non-HCM donors. Our findings therefore strongly indicate that apart from mutation-specific mechanisms, also non-HCM associated allelic-mRNA expression regulation may account for the allelic imbalance of the MYH7 gene in HCM-patients. Since the relative amount of mutant mRNA and protein or the extent of allelic imbalance has been associated with the severity of HCM, individual analysis of the MYH7-allelic expression may provide valuable information for the prognosis of each patient.
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Alelos , Desequilíbrio Alélico , Miosinas Cardíacas , Cardiomiopatia Hipertrófica , Regulação Enzimológica da Expressão Gênica , Cadeias Pesadas de Miosina , Sarcômeros , Adulto , Miosinas Cardíacas/biossíntese , Miosinas Cardíacas/genética , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Cadeias Pesadas de Miosina/biossíntese , Cadeias Pesadas de Miosina/genética , Sarcômeros/genética , Sarcômeros/metabolismo , Sarcômeros/patologiaRESUMO
CONTEXT: Prospective studies have demonstrated the efficacy of osilodrostat in Cushing disease. No study has evaluated osilodrostat in a series of patients with paraneoplastic Cushing syndrome/ectopic adrenocorticotropin syndrome (PNCS/EAS). OBJECTIVE: This work aimed to evaluate in France the real-world efficacy and safety of osilodrostat in patients with PNCS/EAS. METHODS: A total of 33 patients with PNCS/EAS with intense/severe hypercortisolism were involved in this retrospective, multicenter, real-world study. Patients received osilodrostat between May 2019 and March 2022 at a median initial dose (range) of 4 mg/day (1-60) and maximum dose, 20 mg/day (4-100), first under patient then cohort temporary authorizations and after marketing authorization. Regimens used titration (n = 6), block and replace (n = 16), or titration followed by block and replace (n = 11). RESULTS: In 11 patients receiving osilodrostat as first-line monotherapy, median 24-hour urinary free cortisol (24h-UFC) decreased dramatically (from 26 × upper limit of normal [ULN; 2.9-659] to 0.11 × ULN [0.08-14.9]; P < .001). In 9 of them, 24h-UFC normalization was achieved in 2 weeks (median). Thirteen additional patients were previously treated with classic steroidogenesis inhibitors but 10 of these 13 were not controlled. In these patients, osilodrostat monotherapy, used as second line, induced a significantly decreased of 24h-UFC (from 2.6 × ULN [1.1-144] to 0.22 × ULN [0.12-0.66]; P < .01). Nine additional patients received osilodrostat in combination with another anticortisolic drug, decreasing 24h-UFC from 11.8 × ULN (0.3-247) to 0.43 × ULN (0.33-2.4) (P < .01). In parallel, major clinical symptoms/comorbidities improved dramatically with improvement in blood pressure, hyperglycemia, and hypokalemia, allowing the discontinuation or dose reduction of patient treatments. Adrenal insufficiency (grade 3-4) was reported in 8 of 33 patients. CONCLUSION: Osilodrostat is a rapidly efficient therapy for PNCS/EAS with severe/intense hypercortisolism. Osilodrostat was generally well tolerated; adrenal insufficiency was the main side effect.
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Insuficiência Adrenal , Síndrome de Cushing , Humanos , Síndrome de Cushing/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Hormônio Adrenocorticotrópico , Hidrocortisona/uso terapêuticoRESUMO
Objective: Individual goals of health information seeking have been widely neglected by previous research, let alone systematically assessed. The authors propose that these goals may be classified on two dimensions, namely coping focus (problem versus emotion oriented) and regulatory focus (promotion versus prevention oriented).Methods: Based on this classification, the authors developed the 16-item Goals Associated with Health Information Seeking (GAINS) questionnaire measuring the four goals 'understanding', 'action planning', 'hope' and 'reassurance' on four scales, and a superordinate general need for health information. Three studies were conducted to assess the psychometric properties of the questionnaire.Results: In the first two studies (N = 150 and N = 283), internal consistency of the scales was acceptable to very good, and all items had a satisfying discriminatory power. Factorial validity was corroborated by an acceptable model fit in confirmatory factor analyses. In the third study, which included a patient sample (N = 502), the questionnaire proved to be suitable for its target group and nomological relationships with personality as well as with situational variables providing evidence for construct validity.Conclusion: The GAINS is a reliable and valid assessment tool, which enables researchers and practitioners to identify an individual's goals related to health information seeking.
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Informação de Saúde ao Consumidor , Objetivos , Comportamento de Busca de Informação , Inquéritos e Questionários , Adolescente , Adulto , Análise Fatorial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Reprodutibilidade dos Testes , Adulto JovemRESUMO
BACKGROUND: Studies on air pollution and depression in the elderly are limited and the results are heterogeneous. OBJECTIVES: We examined the association of ambient air pollution exposure and diagnosis and symptoms of depression in the elderly; and whether any associations were confounded or modified by cognitive decline. METHODS: We enrolled 821 elderly women from the German SALIA cohort (follow-up examination, 2007-2010). Self-reported depressive symptoms and level of cognition were evaluated using the CESD-R Scale and the CERAD-Plus test, respectively. We used two depression endpoints for analyses: self-reported doctor diagnosis of depression and frequency of depressive symptoms (CESD-R score). Long-term concentrations of particulate matter (PM) size fractions and nitrogen oxides (NOx) modeled by land-use regression were assigned to home addresses. Cross-sectional associations were assessed using adjusted logistic and linear regression models. RESULTS: Concentrations of coarse particles (PMcoarse), fine particles (PM2.5 and PM2.5 abs) and NO2 were significantly associated with diagnosis of depression (e.g. for PM2.5 OR = 1.62, 95%CI: 1.06, 2.46 and for NO2 OR = 1.54, 95% CI: 1.08, 2.19). Similarly, an increase of one interquartile range in PM10, PM2.5, NO2 and NOx was associated with depressive symptoms assessed with the CESD-R score (e.g. for PM2.5 16.2% difference in the mean; 95% CI: 5.8%, 26.5% and for NO2 14.5%; 95% CI: 4.8%, 24.2%). These associations were stronger in women with cognitive decline (e.g. Pint for PM2.5:0.022 and NO2:0.017) compared to women with normal cognition. In addition, living less than 100 m distance to major roads was significantly associated with diagnosis (OR = 1.99, 95% CI: 1.14, 3.47) and symptoms (19.7%; 95% CI: 4.3%, 35.1%) of depression. We did not observe any interaction effect of cognition on prior diagnosis of depression. CONCLUSIONS: Exposure to air pollution was associated with diagnosis of depression and depressive symptoms in elderly women. Women with impaired cognition may be at greater risk of depressive symptoms when exposed to air pollution.
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Poluentes Atmosféricos , Poluição do Ar , Disfunção Cognitiva , Depressão , Idoso , Poluentes Atmosféricos/toxicidade , Estudos Transversais , Depressão/epidemiologia , Exposição Ambiental , Feminino , Humanos , Material ParticuladoRESUMO
Cultivation methods are commonly used in Salmonella surveillance systems and outbreak investigations, and consequently, conclusions about Salmonella evolution and transmission are highly dependent on the performance characteristics of these methods. Past studies have shown that Salmonella serotypes can exhibit different growth characteristics in the same enrichment and selective media. This could lead not only to biased conclusions about the dominant strain present in a sample with mixed Salmonella populations, but also to a low sensitivity for detecting a Salmonella strain in a sample with only a single strain present. The objective of this study was to determine whether cultivation media select preferentially for specific strains of Salmonella in heterogeneous cultures. In this study, four different Salmonella strains (one Salmonella Newport, two Salmonella Typhimurium, and one Salmonella Enteritidis) were competed in a broth-based experiment and a bovine fecal experiment with varied combinations and concentrations of each strain. In all experiments, the strain of Salmonella Newport was the most competitive, regardless of the starting concentration and cultivation protocol. One strain of Salmonella Typhimurium was rarely detected in competition, even when it was the only strain present in bovine feces. Overall, the probability of detecting a specific Salmonella strain had little to do with its starting concentration in the sample. The bias introduced by culture could be dramatically biasing Salmonella surveillance systems and hindering traceback investigations during Salmonella outbreaks. Future studies should focus on the microbiological explanations for this Salmonella interstrain variability, approaches for minimizing the bias, and estimations of the public health significance of this bias.
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Técnicas Bacteriológicas/métodos , Meios de Cultura/química , Surtos de Doenças/prevenção & controle , Salmonella/classificação , Salmonella/isolamento & purificação , Animais , Bovinos , Microbiologia Ambiental , Fezes/microbiologia , Microbiologia de Alimentos , Infecções por Salmonella/epidemiologia , Sensibilidade e EspecificidadeRESUMO
Chemical synthesis of conjugate vaccines, consisting of a polysaccharide linked to a protein, can be technically challenging, and in vivo bacterial conjugations (bioconjugations) have emerged as manufacturing alternatives. Bioconjugation relies upon an oligosaccharyltransferase to attach polysaccharides to proteins, but currently employed enzymes are not suitable for the generation of conjugate vaccines when the polysaccharides contain glucose at the reducing end, which is the case for ~75% of Streptococcus pneumoniae capsules. Here, we use an O-linking oligosaccharyltransferase to generate a polyvalent pneumococcal bioconjugate vaccine with polysaccharides containing glucose at their reducing end. In addition, we show that different vaccine carrier proteins can be glycosylated using this system. Pneumococcal bioconjugates are immunogenic, protective and rapidly produced within E. coli using recombinant techniques. These proof-of-principle experiments establish a platform to overcome limitations of other conjugating enzymes enabling the development of bioconjugate vaccines for many important human and animal pathogens.
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Escherichia coli/genética , Engenharia Genética/métodos , Vacinas Pneumocócicas/genética , Animais , Cápsulas Bacterianas/genética , Cápsulas Bacterianas/imunologia , Escherichia coli/metabolismo , Glicoproteínas/genética , Glicoproteínas/imunologia , Glicoproteínas/isolamento & purificação , Glicosilação , Humanos , Vacinas Pneumocócicas/isolamento & purificação , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/imunologia , Vacinas Conjugadas/genética , Vacinas Conjugadas/isolamento & purificação , Vacinas Sintéticas/genética , Vacinas Sintéticas/isolamento & purificaçãoRESUMO
No recent study has focused on clinical features of subclinical hypothyroidism (SCH), especially in older patients. TSH measurement has remarkably evolved these last 20 years and thus reconsideration is needed. In our prospective multicenter study (2012-2014) including 807 subjects aged <60 years (<60y) and 531 subjects ≥60 years (≥60y), we have monitored 11 hypothyroidism-related clinical signs (hCS) together with TSH, FT4, FT3 and anti-thyroperoxidase antibodies values. hCS expression has been compared in patients with SCH vs euthyroidism in each age group. The number of hCS above 60y of age were found to be more elevated in the euthyroid population (1.9 vs 1.6, p<0.01) than in the SCH population (2.3 vs 2.6, p=0.41) while increase in hCS is limited to SCH subjects in the <60y group (p<0.01). The percentage of subjects with at least 3 signs increased with SCH in the <60y group (42.6% vs 25.0%, p<0.01) but not ≥60y (34.4% vs 33.9%, p=0.96). In older individuals, only three hCS could be related to both SCH and a decreased T3/T4-ratio (0.26 vs 0.27, p<0.01), suggesting either a reduced activity of TSH, or an adaptive response with aging. While hCS are clearly associated with SCH in patients <60y, they are not so informative in older subjects. TSH measurements carried out on the basis of hCS need to be interpreted with caution in aged patients. A reassessment of the TSH reference range in older patients is clearly needed and should be associated to more appropriate monitoring of thyroid dysfunction.
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Epidemiologic investigations often report dose-response associations, which may be combined in meta-analyses. The authors examined how often the log odds, risk, or hazard ratio per unit increase in exposure, and its standard error, can be estimated from results reported from observational studies of diet and prostate or bladder cancer so that results are usable in meta-analyses estimating dose-response associations. Eight electronic databases were searched for studies reporting on the association of diet, nutrition, or physical activity with these cancers. A total of 767 papers reported 3,284 results; 1,999 (61%) results, reported in 545 (71%) papers, were usable in dose-response meta-analyses. The most important reason that results were not usable was the absence of sufficient information on exposure levels in the different groups. The proportion of results usable in "high-low" meta-analyses (comparisons of extreme categories) was similar (62%). Results that showed evidence of an association were more likely to be usable than results that found no such evidence. Insufficient detail in reporting of results of observational studies can lead to exclusion of these results from meta-analyses and is an important threat to the validity of systematic reviews of such research. Results providing evidence of associations may be overrepresented in meta-analyses of observational studies.
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Dieta/estatística & dados numéricos , Relação Dose-Resposta a Droga , Neoplasias da Próstata/etiologia , Viés de Publicação/estatística & dados numéricos , Neoplasias da Bexiga Urinária/etiologia , Estudos de Casos e Controles , Bases de Dados como Assunto , Humanos , MasculinoRESUMO
BACKGROUND: The cognitive incongruity model of epistemic beliefs and emotions states that if students' beliefs about the nature of knowledge (e.g., knowledge as simple and absolute) are incompatible with the epistemic nature of learning materials (e.g., complex and contradictory), cognitive incongruity arises. This, in turn, entails negative emotional consequences. AIMS: The epistemic nature of contradictory learning materials might be perceived differently depending on whether individuals resolve the contradictions or not. Therefore, extending the cognitive incongruity model, the present paper argues that cognitive (in)congruity also depends on how individuals act on the learning materials. We expect that only if students resolve contradictory scientific claims (e.g., by identifying moderators), more advanced epistemic beliefs (e.g., evaluativism) have positive emotional effects and vice versa. SAMPLE: A field-experimental study with N = 86 undergraduate psychology students was conducted. METHOD: Using a multiple-texts approach, participants were first presented controversial evidence on gender stereotyping from 18 different (fictional) studies. In contrast to similar multiple-texts approaches, all contradictions could be resolved by identifying the contextual factors that a certain type of stereotype discrimination occurs in ('resolvable controversies'). After reading, the experimental group was asked to resolve the contradictions, whereas two control groups read the same texts, but were not required to resolve the controversies. RESULTS: Results revealed that absolute beliefs positively and evaluativistic beliefs negatively predict negative emotions, but only if students were instructed to resolve the contradictions. CONCLUSIONS: Our results suggest that extending the cognitive incongruity model by how students deal with controversial learning materials might be worthwhile.
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Atitude , Emoções/fisiologia , Aprendizagem/fisiologia , Modelos Psicológicos , Pensamento/fisiologia , Adulto , Dissonância Cognitiva , Conflito Psicológico , Feminino , Humanos , Masculino , Estereotipagem , Adulto JovemRESUMO
The Norovirus genus contains important human pathogens, but the role of host pathways in norovirus replication is largely unknown. Murine noroviruses provide the opportunity to study norovirus replication in cell culture and in small animals. The human norovirus nonstructural protein NS1/2 interacts with the host protein VAMP-associated protein A (VAPA), but the significance of the NS1/2-VAPA interaction is unexplored. Here we report decreased murine norovirus replication in VAPA- and VAPB-deficient cells. We characterized the role of VAPA in detail. VAPA was required for the efficiency of a step(s) in the viral replication cycle after entry of viral RNA into the cytoplasm but before the synthesis of viral minus-sense RNA. The interaction of VAPA with viral NS1/2 proteins is conserved between murine and human noroviruses. Murine norovirus NS1/2 directly bound the major sperm protein (MSP) domain of VAPA through its NS1 domain. Mutations within NS1 that disrupted interaction with VAPA inhibited viral replication. Structural analysis revealed that the viral NS1 domain contains a mimic of the phenylalanine-phenylalanine-acidic-tract (FFAT) motif that enables host proteins to bind to the VAPA MSP domain. The NS1/2-FFAT mimic region interacted with the VAPA-MSP domain in a manner similar to that seen with bona fide host FFAT motifs. Amino acids in the FFAT mimic region of the NS1 domain that are important for viral replication are highly conserved across murine norovirus strains. Thus, VAPA interaction with a norovirus protein that functionally mimics host FFAT motifs is important for murine norovirus replication.IMPORTANCE Human noroviruses are a leading cause of gastroenteritis worldwide, but host factors involved in norovirus replication are incompletely understood. Murine noroviruses have been studied to define mechanisms of norovirus replication. Here we defined the importance of the interaction between the hitherto poorly studied NS1/2 norovirus protein and the VAPA host protein. The NS1/2-VAPA interaction is conserved between murine and human noroviruses and was important for early steps in murine norovirus replication. Using structure-function analysis, we found that NS1/2 contains a short sequence that molecularly mimics the FFAT motif that is found in multiple host proteins that bind VAPA. This represents to our knowledge the first example of functionally important mimicry of a host FFAT motif by a microbial protein.
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Interações Hospedeiro-Patógeno , Norovirus/fisiologia , Fenilalanina/química , Proteínas de Transporte Vesicular/metabolismo , Proteínas não Estruturais Virais/química , Replicação Viral , Motivos de Aminoácidos , Animais , Linhagem Celular , Células HEK293 , Humanos , Camundongos , Norovirus/genética , Células RAW 264.7 , RNA Viral/genética , Genética Reversa , Proteínas de Transporte Vesicular/genética , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismoRESUMO
BACKGROUND: Particularly in higher education, not only a view of science as a means of finding absolute truths (absolutism), but also a view of science as generally tentative (multiplicism) can be unsophisticated and obstructive for learning. Most quantitative epistemic belief inventories neglect this and understand epistemic sophistication as disagreement with absolute statements. AIMS: This article suggests considering absolutism and multiplicism as separate dimensions. Following our understanding of epistemic sophistication as a cautious and reluctant endorsement of both positions, we assume evaluativism (a contextually adaptive view of knowledge as personally constructed and evidence-based) to be reflected by low agreement with both generalized absolute and generalized multiplicistic statements. SAMPLES: Three studies with a total sample size of N = 416 psychology students were conducted. METHODS: A domain-specific inventory containing both absolute and multiplicistic statements was developed. Expectations were tested by exploratory factor analysis, confirmatory factor analysis, and correlational analyses. RESULTS: Results revealed a two-factor solution with an absolute and a multiplicistic factor. Criterion validity of both factors was confirmed. Cross-sectional analyses revealed that agreement to generalized multiplicistic statements decreases with study progress. Moreover, consistent with our understanding of epistemic sophistication as a reluctant attitude towards generalized epistemic statements, evidence for a negative relationship between epistemic sophistication and need for cognitive closure was found. CONCLUSIONS: We recommend including multiplicistic statements into epistemic belief questionnaires and considering them as a separate dimension, especially when investigating individuals in later stages of epistemic development (i.e., in higher education).
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Cultura , Conhecimento , Estudantes/psicologia , Pensamento , Adulto , Humanos , Universidades , Adulto JovemRESUMO
Inflammatory bowel disease (IBD) is associated with risk variants in the human genome and dysbiosis of the gut microbiome, though unifying principles for these findings remain largely undescribed. The human commensal Bacteroides fragilis delivers immunomodulatory molecules to immune cells via secretion of outer membrane vesicles (OMVs). We reveal that OMVs require IBD-associated genes, ATG16L1 and NOD2, to activate a noncanonical autophagy pathway during protection from colitis. ATG16L1-deficient dendritic cells do not induce regulatory T cells (T(regs)) to suppress mucosal inflammation. Immune cells from human subjects with a major risk variant in ATG16L1 are defective in T(reg) responses to OMVs. We propose that polymorphisms in susceptibility genes promote disease through defects in "sensing" protective signals from the microbiome, defining a potentially critical gene-environment etiology for IBD.
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Bacteroides fragilis/imunologia , Proteínas de Transporte/genética , Microbioma Gastrointestinal/imunologia , Interação Gene-Ambiente , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/microbiologia , Proteína Adaptadora de Sinalização NOD2/genética , Adulto , Idoso , Animais , Autofagia/imunologia , Proteínas Relacionadas à Autofagia , Células Dendríticas/imunologia , Vesículas Extracelulares/imunologia , Feminino , Predisposição Genética para Doença , Genoma Humano , Humanos , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Polimorfismo Genético , Linfócitos T Reguladores/imunologiaRESUMO
We investigated the presence of autoantibodies (aAbs) directed against the parathyroid gland in 17 patients with spontaneous isolated acquired hypoparathyroidism. Fourteen patients with acquired hypoparathyroidism (AH) associated with type I or II autoimmune polyendocrinopathy syndrome were also tested in comparison with a control group of 68 subjects without AH, including patients with other autoimmune diseases and healthy blood donors. aAbs against parathyroid tissue were screened using an indirect immunofluorescence technique on primate parathyroid tissue and human parathyroid adenoma. aAbs against the calcium-sensing receptor (CaSR) were analyzed using an immunoblotting assay with the recombinant extracellular domain of the human CaSR as antigen. Seven of the 31 patients with AH were positive for CaSR aAbs. Five of the positive sera were obtained from the group with isolated AH. The two other positive sera were from patients with autoimmune polyendocrinopathy syndrome. The sensitivity of the immunoblotting technique was higher than that of both the radioimmunological test using the extracellular domain of the CaSR and the indirect immunofluorescence technique. There were no positive sera in the control group. In conclusion, using an immunoblotting assay, we demonstrate the presence of CaSR aAbs in about one third of the patients with isolated AH, pointing out the value of detecting such aAbs to assess the autoimmune origin of the disease.
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Autoanticorpos/sangue , Hipoparatireoidismo/imunologia , Receptores de Detecção de Cálcio/imunologia , Adolescente , Adulto , Idoso , Biomarcadores , Criança , Feminino , Humanos , Hipoparatireoidismo/diagnóstico , Immunoblotting , Masculino , Pessoa de Meia-IdadeRESUMO
Pregnant women in the third trimester are at increased risk of severe influenza disease relative to the general population, though mechanisms behind this are not completely understood. The immune response to influenza infection employs both complement (C') and antibody (Ab). The relative contributions of these components to the anti-viral response are difficult to dissect because most humans have pre-existing influenza-specific Abs. We developed the African green monkey (AGM) as a tractable nonhuman primate model to study changes in systemic innate immunity to influenza during pregnancy. Because the AGMs were influenza-naïve, we were able to examine the role of C' in influenza virus neutralization using serum from non-pregnant animals before and after influenza infection. We determined that serum from naïve AGMs neutralized influenza via C', while post-infection neutralization did not require C', suggesting an Ab-mediated mechanism. The latter mimicked neutralization using human serum. Further, we found that ex vivo neutralization of influenza with both naïve and influenza-immune AGM serum occurred by virus particle aggregation and lysis, with immune serum lysing virus at a much higher rate than naïve serum. We hypothesized that the anti-influenza C' response would diminish late in AGM pregnancy, corresponding with the time when pregnant women suffer increased influenza severity. We found that influenza neutralization capacity is significantly diminished in serum collected late in the third trimester. Strikingly, we found that circulating levels of C3, C3a, and C4 are diminished late in gestation relative to nonpregnant animals, and while neutralization capacity and serum C3a return to normal shortly after parturition, C3 and C4 levels do not. This AGM model system will enable further studies of the role of physiologic and hormonal changes in downregulating C'-mediated anti-viral immunity during pregnancy, and it will permit the identification of therapeutic targets to improve outcomes of influenza virus infection in pregnant women.
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Proteínas do Sistema Complemento/metabolismo , Vírus da Influenza A Subtipo H1N1/imunologia , Terceiro Trimestre da Gravidez/sangue , Terceiro Trimestre da Gravidez/imunologia , Animais , Linhagem Celular , Chlorocebus aethiops , Feminino , Humanos , Imunização , Testes de Neutralização , Gravidez , Especificidade da EspécieRESUMO
The African Green Monkey (AGM) model was used to analyze the role of complement in neutralization of parainfluenza virus. Parainfluenza virus 5 (PIV5) and human parainfluenza virus type 2 were effectively neutralized in vitro by naïve AGM sera, but neutralizing capacity was lost by heat-inactivation. The mechanism of neutralization involved formation of massive aggregates, with no evidence of virion lysis. Following inoculation of the respiratory tract with a PIV5 vector expressing HIV gp160, AGM produced high levels of serum and tracheal antibodies against gp120 and the viral F and HN proteins. However, in the absence of complement these anti-PIV5 antibodies had very poor neutralizing capacity. Virions showed extensive deposition of IgG and C1q with post- but not pre-immune sera. These results highlight the importance of complement in the initial antibody response to parainfluenza viruses, with implications for understanding infant immune responses and design of vaccine strategies for these pediatric pathogens.
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Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Chlorocebus aethiops , Complemento C1q/imunologia , Vírus da Parainfluenza 2 Humana/imunologia , Vírus da Parainfluenza 5/imunologia , Infecções por Paramyxoviridae/imunologia , Animais , Chlorocebus aethiops/imunologia , Chlorocebus aethiops/virologia , Modelos Animais de Doenças , Humanos , Testes de Neutralização , Vírus da Parainfluenza 2 Humana/fisiologia , Vírus da Parainfluenza 5/fisiologia , Infecções por Paramyxoviridae/virologiaRESUMO
Macrophages are an important cell type for regulation of immunity, and can play key roles in virus pathogenesis. Here we address the effect of infection of primary human macrophages with the related paramyxoviruses Parainfluenza virus 5 (PIV5) and Mumps virus (MuV). Monocyte-derived macrophages infected with PIV5 or MuV showed very little cytopathic effect, but were found to be defective in migration toward a gradient of chemokines such as macrophage colony stimulating factor (MCSF) and vascular endothelial growth factor (VEGF). For MuV infection, the inhibition of migration required live virus infection, but was not caused by a loss of chemokine receptors on the surface of infected cells. MuV-mediated inhibition of macrophage chemotaxis was through a soluble factor released from infected cells. MuV infection enhanced secretion of TNF-α, but not macrophage inhibitory factor (MIF). Antibody inhibition and add-back experiments demonstrated that TNF-α was both necessary and sufficient for MuV-mediate chemotaxis inhibition.
Assuntos
Inibição de Migração Celular/efeitos dos fármacos , Macrófagos/virologia , Vírus da Caxumba/fisiologia , Respirovirus/fisiologia , Fator de Necrose Tumoral alfa/farmacologia , Quimiotaxia/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Humanos , Evasão da Resposta Imune , Oxirredutases Intramoleculares/metabolismo , Fator Estimulador de Colônias de Macrófagos/imunologia , Fator Estimulador de Colônias de Macrófagos/farmacologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Macrófagos/imunologia , Cultura Primária de Células , Receptores de Quimiocinas/imunologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/imunologia , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
During 2009, 616 bats representing at least 22 species were collected from 10 locations throughout Kenya. A new lyssavirus, named Shimoni bat virus (SHIBV), was isolated from the brain of a dead Commerson's leaf-nosed bat (Hipposideros commersoni), found in a cave in the coastal region of Kenya. Genetic distances and phylogenetic reconstructions, implemented for each gene and for the concatenated alignment of all five structural genes (N, P, M, G and L), demonstrated that SHIBV cannot be identified with any of the existing species, but rather should be considered an independent species within phylogroup II of the Lyssavirus genus, most similar to Lagos bat virus (LBV). Antigenic reaction patterns with anti-nucleocapsid monoclonal antibodies corroborated these distinctions. In addition, new data on the diversity of LBV suggests that this species may be subdivided quantitatively into three separate genotypes. However, the identity values alone are not considered sufficient criteria for demarcation of new species within LBV.
Assuntos
Quirópteros/virologia , Lyssavirus/classificação , Lyssavirus/isolamento & purificação , Infecções por Rhabdoviridae/veterinária , Animais , Encéfalo/virologia , Análise por Conglomerados , Quênia , Lyssavirus/genética , Dados de Sequência Molecular , Filogenia , Polimorfismo Genético , Infecções por Rhabdoviridae/virologia , Análise de Sequência de DNA , Proteínas Virais/genéticaRESUMO
The immune response elicited by LC16m8, a candidate smallpox vaccine that was developed in Japan by cold selection during serial passage of the Lister vaccine virus in primary rabbit kidney cells, was compared to Dryvax in a mouse model. LC16m8 carries a mutation resulting in the truncation of the B5 protein, an important neutralizing target of the extracellular envelope form of vaccinia virus (EV). LC16m8 elicited a broad-spectrum immunoglobulin G (IgG) response that neutralized both EV and the intracellular mature form of vaccinia virus and provoked cell-mediated immune responses, including the activation of CD4+ and CD8+ cells, similarly to Dryvax. Mice inoculated with LC16m8 had detectable but low levels of anti-B5 IgG compared to Dryvax, but both Dryvax and LC16m8 sera neutralized vaccinia virus EV in vitro. A truncated B5 protein (approximately 8 kDa) was expressed abundantly in LC16m8-infected cells, and both murine immune sera and human vaccinia virus immunoglobulin recognized the truncated recombinant B5 protein in antigen-specific enzyme-linked immunosorbent assays. At a high-dose intranasal challenge (100 or 250 50% lethal doses), LC16m8 and Dryvax conferred similar levels of protection against vaccinia virus strain WR postvaccination. Taken together, the results extend our current understanding of the protective immune responses elicited by LC16m8 and indicate that the relative efficacy in a mouse model rivals that of previously licensed smallpox vaccines.