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BACKGROUND: The beneficial off-target effects of Bacille Calmette-Guérin (BCG) vaccination potentially include protection against allergy. OBJECTIVE: In the MIS BAIR trial, we aimed to determine whether neonatal BCG vaccination reduces atopic sensitisation and clinical food allergy in infants. METHODS: In this randomised controlled trial, 1272 neonates were allocated to BCG-Denmark vaccine (0.05 mL intradermal dose) or no BCG at birth. Randomisation was stratified by recruitment site, mode of delivery and plurality of birth. The primary outcome was the incidence of atopic sensitisation determined by skin prick test at 1 year of age. Food allergy was determined by 3-monthly online questionnaires and oral food challenges. Data were analysed by intention-to-treat using binary regression. CLINICALTRIALS: gov (NCT01906853). RESULTS: Atopic sensitisation during the first year of life was 22.9% among infants in the BCG group and 18.9% in the control group (adjusted risk difference (aRD) 3.8% (95% CI -1.5 to 9.1) after multiple imputation). Clinical food allergy was similar between infants in the BCG and control groups (9.8% vs. 9.6%; aRD 0.2, 95% CI -3.4 to 3.8). An interaction was observed between the primary outcome and maternal history of BCG vaccination. No interaction was observed for the additional prespecified potential effect modifiers tested (sex, delivery mode, family history of any allergy, season of birth, hepatitis B vaccination at randomisation, BCG scar and age at BCG administration). CONCLUSIONS AND CLINICAL RELEVANCE: Neonatal BCG-Denmark vaccination does not protect against atopic sensitisation or clinical food allergy in the first year of life.
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Typical (or classic) Rett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by a period of regression, partial or complete loss of purposeful hand movements, and acquired speech, impaired gait, and stereotyped hand movements. In over 95% of typical RTT, a pathogenic variant is found in the methyl-CPG binding protein 2 gene (MECP2). Here, we describe a young woman with clinically diagnosed typical RTT syndrome who lacked a genetic diagnosis despite 20 years of investigation and multiple rounds of sequencing the MECP2 gene. Recently, additional genetic testing using next-generation sequencing was completed, which revealed a partial insertion of the BCL11A gene within exon 4 of MECP2, resulting in a small deletion in MECP2, causing likely disruption of MeCP2 function due to a frameshift. This case demonstrates the ever-changing limitations of genetic testing, as well as the importance of continual pursuit of a diagnosis as technologies improve and are more widely utilized.
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Krabbe disease is a rare autosomal recessive neurodegenerative disease, caused by mutations in the GALC gene, which encodes for the lysosomal enzyme galactocerebrosidase. Typical clinical manifestations of Krabbe include psychomotor deterioration, visual loss, seizures, and spasticity, that result from central nervous system demyelination. We report a case of a 35-year-old male with Krabbe who presented in adulthood with isolated severe, upper extremity predominant demyelinating sensorimotor polyneuropathy and did not develop other distinguishing clinical or radiological features of Krabbe until the later stages of the disease. The patient's diagnostic odyssey lasted 13 years from presentation to diagnosis, which was ultimately determined with the use of whole exome sequencing (WES) at the age of 48 years. The expanding phenotypic spectrum of adult-onset Krabbe Disease (AOKD) presents a diagnostic challenge that can lead to diagnostic delays and potentially affect treatment options. Our patient's case underscores the importance of pursuing WES in those with undiagnosed progressive neuromuscular disorders.
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Leucodistrofia de Células Globoides , Doenças Neurodegenerativas , Polineuropatias , Adulto , Masculino , Humanos , Pessoa de Meia-Idade , Leucodistrofia de Células Globoides/complicações , Leucodistrofia de Células Globoides/diagnóstico , Leucodistrofia de Células Globoides/genética , Galactosilceramidase , MutaçãoRESUMO
The KDM4/JMJD2 family of histone demethylases is amplified in human cancers. However, little is known about their physiologic or tumorigenic roles. We have identified a conserved and unappreciated role for the JMJD2A/KDM4A H3K9/36 tridemethylase in cell cycle progression. We demonstrate that JMJD2A protein levels are regulated in a cell cycle-dependent manner and that JMJD2A overexpression increased chromatin accessibility, S phase progression, and altered replication timing of specific genomic loci. These phenotypes depended on JMJD2A enzymatic activity. Strikingly, depletion of the only C. elegans homolog, JMJD-2, slowed DNA replication and increased ATR/p53-dependent apoptosis. Importantly, overexpression of HP1γ antagonized JMJD2A-dependent progression through S phase, and depletion of HPL-2 rescued the DNA replication-related phenotypes in jmjd-2(-/-) animals. Our findings describe a highly conserved model whereby JMJD2A regulates DNA replication by antagonizing HP1γ and controlling chromatin accessibility.
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Ciclo Celular , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Imunoprecipitação da Cromatina , Proteínas Cromossômicas não Histona/antagonistas & inibidores , Proteínas Cromossômicas não Histona/genética , Replicação do DNA , Citometria de Fluxo , Células HeLa , Humanos , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , TransfecçãoRESUMO
Apical membrane Ag 1 (AMA1) is one of the leading candidate Ags for inclusion in a subunit vaccine against blood-stage malaria. However, the efficacy of Ab-inducing recombinant AMA1 protein vaccines in phase IIa/b clinical trials remains disappointing. In this article, we describe the development of recombinant human adenovirus serotype 5 and modified vaccinia virus Ankara vectors encoding AMA1 from the Plasmodium chabaudi chabaudi strain AS. These vectors, when used in a heterologous prime-boost regimen in BALB/c mice, are capable of inducing strong transgene-specific humoral and cellular immune responses. We show that this vaccination regimen is protective against a nonlethal P. chabaudi chabaudi strain AS blood-stage challenge, resulting in reduced peak parasitemias. The role of vaccine-induced, AMA1-specific Abs and T cells in mediating the antiparasite effect was investigated by in vivo depletion of CD4(+) T cells and adoptive-transfer studies into naive and immunodeficient mice. Depletion of CD4(+) T cells led to a loss of vaccine-induced protection. Adoptive-transfer studies confirmed that efficacy is mediated by both CD4(+) T cells and Abs functioning in the context of an intact immune system. Unlike previous studies, these results confirm that Ag-specific CD4(+) T cells, induced by a clinically relevant vaccine-delivery platform, can make a significant contribution to vaccine blood-stage efficacy in the P. chabaudi model. Given that cell-mediated immunity may also contribute to parasite control in human malaria, these data support the clinical development of viral-vectored vaccines that induce both T cell and Abs against Plasmodium falciparum blood-stage malaria Ags like AMA1.
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Adenovírus Humanos/imunologia , Antígenos de Protozoários/genética , Vacinas Antimaláricas/genética , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Proteínas de Membrana/genética , Plasmodium falciparum/imunologia , Proteínas de Protozoários/genética , Adenovírus Humanos/genética , Animais , Anticorpos Antiprotozoários/biossíntese , Anticorpos Antiprotozoários/sangue , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/sangue , Antígenos de Protozoários/sangue , Antígenos de Protozoários/imunologia , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/imunologia , Humanos , Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/sangue , Malária Falciparum/prevenção & controle , Proteínas de Membrana/sangue , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Nus , Dados de Sequência Molecular , Plasmodium chabaudi/genética , Plasmodium chabaudi/imunologia , Plasmodium falciparum/genética , Proteínas de Protozoários/sangue , Proteínas de Protozoários/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/genética , Vacinas de Subunidades Antigênicas/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vaccinia virus/genética , Vaccinia virus/imunologiaRESUMO
International sharing of genomic data files arising from clinical testing of patients is essential to further improve genomic medicine. Whilst the general public are reluctant to donate DNA for research, the choices patients actually make about sharing their clinical genomic data for future re-use (research or clinical) are unknown. We ascertained the data-sharing choices of 1515 patients having genomic testing for inherited conditions or cancer treatment from clinical consent forms. To understand the experiences and preferences of these patients, surveys were administered after test consent (RR 73%). Almost all patients (98%) consented to share their data. Survey respondents' decision recall was high (90%), but poorer if English was an additional language (p < 0.001). Parents deciding on behalf of children were over-represented amongst data-sharing decliners (p = 0.047) and decliners were more likely to believe that stored data could be easily reidentified (p < 0.001). A quarter of respondents did not know if reidentification would be easy and 44% of them were concerned about this possibility. Of those willing to share data overseas (60%), 23% indicated the recipient researcher's country would affect their decision. Most respondents (89%) desired some ongoing control over research use of their data. Four preliminary data-sharing profiles emerged; their further development could inform tailored patient resources. Our results highlight considerations for establishment of systems to make clinical genomic data files available for reanalysis locally and across borders. Patients' willingness to share their data - and value of the resulting research - should encourage clinical laboratories to consider sharing data systematically for secondary uses.
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Testes Genéticos , Disseminação de Informação , Humanos , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Feminino , Masculino , Tomada de Decisões , Genômica/métodos , Adulto , Pessoa de Meia-Idade , Inquéritos e Questionários , Adolescente , Consentimento Livre e EsclarecidoRESUMO
Replication-deficient adenovirus and modified vaccinia virus Ankara (MVA) vectors expressing single pre-erythrocytic or blood-stage Plasmodium falciparum Ags have entered clinical testing using a heterologous prime-boost immunization approach. In this study, we investigated the utility of the same immunization regimen when combining viral vectored vaccines expressing the 42-kDa C terminus of the blood-stage Ag merozoite surface protein 1 and the pre-erythrocytic Ag circumsporozoite protein in the Plasmodium yoelii mouse model. We find that vaccine coadministration leads to maintained Ab responses and efficacy against blood-stage infection, but reduced secondary CD8(+) T cell responses against both Ags and efficacy against liver-stage infection. CD8(+) T cell interference can be minimized by coadministering the MVA vaccines at separate sites, resulting in enhanced liver-stage efficacy in mice immunized against both Ags compared with just one. CD8(+) T cell interference (following MVA coadministration as a mixture) may be caused partly by a lack of physiologic space for high-magnitude responses against multiple Ags, but is not caused by competition for presentation of Ag on MHC class I molecules, nor is it due to restricted T cell access to APCs presenting both Ags. Instead, enhanced killing of peptide-pulsed cells is observed in mice possessing pre-existing T cells against two Ags compared with just one, suggesting that priming against multiple Ags may in part reduce the potency of multiantigen MVA vectors to stimulate secondary CD8(+) T cell responses. These data have important implications for the development of a multistage or multicomponent viral vectored malaria vaccine for use in humans.
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Antígenos de Protozoários/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Adenoviridae/genética , Animais , Linfócitos T CD8-Positivos/parasitologia , Modelos Animais de Doenças , Feminino , Vetores Genéticos , Malária Falciparum/prevenção & controle , Proteína 1 de Superfície de Merozoito/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Plasmodium falciparum/imunologia , Vaccinia virus/genéticaRESUMO
Identification of correlates of protection for infectious diseases including malaria is a major challenge and has become one of the main obstacles in developing effective vaccines. We investigated protection against liver-stage malaria conferred by vaccination with adenoviral (Ad) and modified vaccinia Ankara (MVA) vectors expressing pre-erythrocytic malaria Ags. By classifying CD8(+) T cells into effector, effector memory (T(EM)), and central memory subsets using CD62L and CD127 markers, we found striking differences in T cell memory generation. Although MVA induced accelerated central memory T cell generation, which could be efficiently boosted by subsequent Ad administration, it failed to protect against malaria. In contrast, Ad vectors, which permit persistent Ag delivery, elicit a prolonged effector T cell and T(EM) response that requires long intervals for an efficient boost. A preferential T(EM) phenotype was maintained in liver, blood, and spleen after Ad/MVA prime-boost regimens, and animals were protected against malaria sporozoite challenge. Blood CD8(+) T(EM) cells correlated with protection against malaria liver-stage infection, assessed by estimation of number of parasites emerging from the liver into the blood. The protective ability of Ag-specific T(EM) cells was confirmed by transfer experiments into naive recipient mice. Thus, we identify persistent CD8 T(EM) populations as essential for vaccine-induced pre-erythrocytic protection against malaria, a finding that has important implications for vaccine design.
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Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/parasitologia , Memória Imunológica , Hepatopatias Parasitárias/imunologia , Hepatopatias Parasitárias/prevenção & controle , Malária/imunologia , Malária/prevenção & controle , Adenoviridae/genética , Adenoviridae/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/imunologia , Vetores Genéticos/uso terapêutico , Antígenos H-2/administração & dosagem , Antígenos H-2/genética , Antígenos H-2/imunologia , Humanos , Memória Imunológica/genética , Hepatopatias Parasitárias/patologia , Malária/patologia , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/genética , Vacinas Antimaláricas/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Plasmodium berghei/genética , Plasmodium berghei/imunologia , Proteínas de Protozoários/administração & dosagem , Proteínas de Protozoários/genética , Proteínas de Protozoários/imunologia , Transgenes/imunologia , Vacínia/genética , Vacínia/imunologiaRESUMO
A central goal in vaccinology is the induction of high and sustained Ab responses. Protein-in-adjuvant formulations are commonly used to achieve such responses. However, their clinical development can be limited by the reactogenicity of some of the most potent preclinical adjuvants and the cost and complexity of licensing new adjuvants for human use. Also, few adjuvants induce strong cellular immunity, which is important for protection against many diseases, such as malaria. We compared classical adjuvants such as aluminum hydroxide to new preclinical adjuvants and adjuvants in clinical development, such as Abisco 100, CoVaccine HT, Montanide ISA720, and stable emulsion-glucopyranosyl lipid A, for their ability to induce high and sustained Ab responses and T cell responses. These adjuvants induced a broad range of Ab responses when used in a three-shot protein-in-adjuvant regimen using the model Ag OVA and leading blood-stage malaria vaccine candidate Ags. Surprisingly, this range of Ab immunogenicity was greatly reduced when a protein-in-adjuvant vaccine was used to boost Ab responses primed by a human adenovirus serotype 5 vaccine recombinant for the same Ag. This human adenovirus serotype 5-protein regimen also induced a more cytophilic Ab response and demonstrated improved efficacy of merozoite surface protein-1 protein vaccines against a Plasmodium yoelii blood-stage challenge. This indicates that the differential immunogenicity of protein vaccine adjuvants may be largely overcome by prior immunization with recombinant adenovirus, especially for adjuvants that are traditionally considered poorly immunogenic in the context of subunit vaccination and may circumvent the need for more potent chemical adjuvants.
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Adenoviridae/imunologia , Adjuvantes Imunológicos/farmacologia , Vacinas Antimaláricas/imunologia , Vacinação/métodos , Animais , Ensaio de Imunoadsorção Enzimática , Feminino , Imunoglobulina G/análise , Imunoglobulina G/imunologia , Proteína 1 de Superfície de Merozoito/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
Factors and processes determining heterogeneous ('patchy') population distributions in natural environments have long been a major focus in ecology. Existing theoretical approaches proved to be successful in explaining vegetation patterns. In the case of animal populations, existing theories are at most conceptual: they may suggest a qualitative explanation but largely fail to explain patchiness quantitatively. We aim to bridge this knowledge gap. We present a new mechanism of self-organized formation of a patchy spatial population distribution. A factor that was under-appreciated by pattern formation theories is animal sociability, which may result in density dependent movement behaviour. Our approach was inspired by a recent project on movement and distribution of slugs in arable fields. The project discovered a strongly heterogeneous slug distribution and a specific density dependent individual movement. In this paper, we bring these two findings together. We develop a model of density dependent animal movement to account for the switch in the movement behaviour when the local population density exceeds a certain threshold. The model is fully parameterized using the field data. We then show that the model produces spatial patterns with properties closely resembling those observed in the field, in particular to exhibit similar values of the aggregation index.
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BACKGROUND: Human immunoglobulin G (IgG) plays an important role in mediating protective immune responses to malaria. Although human serum immunoglobulin A (IgA) is the second most abundant class of antibody in the circulation, its contribution, if any, to protective responses against malaria is not clear. RESULTS: To explore the mechanism(s) by which IgA may mediate a protective effect, we generated fully human IgA specific for the C-terminal 19-kDa region of Plasmodium falciparum merozoite surface protein 1 (PfMSP1 19), a major target of protective immune responses. This novel human IgA bound antigen with an affinity comparable to that seen for an epitope-matched protective human IgG1. Furthermore, the human IgA induced significantly higher NADPH-mediated oxidative bursts and degranulation from human neutrophils than the epitope-matched human IgG1 from which it was derived. Despite showing efficacy in in vitro functional assays, the human IgA failed to protect against parasite challenge in vivo in mice transgenic for the human Fcα receptor (FcαRI/CD89). A minority of the animals treated with IgA, irrespective of FcαRI expression, showed elevated serum TNF-α levels and concomitant mouse anti-human antibody (MAHA) responses. CONCLUSIONS: The lack of protection afforded by MSP1 19-specific IgA against parasite challenge in mice transgenic for human FcαRI suggests that this antibody class does not play a major role in control of infection. However, we cannot exclude the possibility that protective capacity may have been compromised in this model due to rapid clearance and inappropriate bio-distribution of IgA, and differences in FcαRI expression profile between humans and transgenic mice.
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Anticorpos Antiprotozoários/imunologia , Imunoglobulina A/imunologia , Proteína 1 de Superfície de Merozoito/imunologia , Plasmodium falciparum/imunologia , Proteínas Recombinantes/imunologia , Animais , Antígenos CD/genética , Modelos Animais de Doenças , Humanos , Imunização Passiva , Imunoglobulina G/metabolismo , Malária/imunologia , Malária/prevenção & controle , Camundongos , Camundongos Transgênicos , NADPH Oxidases/metabolismo , Plasmodium berghei , Receptores Fc/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Adjuvants are substances that enhance immune responses and thus improve the efficacy of vaccination. Few adjuvants are available for use in humans, and the one that is most commonly used (alum) often induces suboptimal immunity for protection against many pathogens. There is thus an obvious need to develop new and improved adjuvants. We have therefore taken an approach to adjuvant discovery that uses in silico modeling and structure-based drug-design. As proof-of-principle we chose to target the interaction of the chemokines CCL22 and CCL17 with their receptor CCR4. CCR4 was posited as an adjuvant target based on its expression on CD4(+)CD25(+) regulatory T cells (Tregs), which negatively regulate immune responses induced by dendritic cells (DC), whereas CCL17 and CCL22 are chemotactic agents produced by DC, which are crucial in promoting contact between DC and CCR4(+) T cells. Molecules identified by virtual screening and molecular docking as CCR4 antagonists were able to block CCL22- and CCL17-mediated recruitment of human Tregs and Th2 cells. Furthermore, CCR4 antagonists enhanced DC-mediated human CD4(+) T cell proliferation in an in vitro immune response model and amplified cellular and humoral immune responses in vivo in experimental models when injected in combination with either Modified Vaccinia Ankara expressing Ag85A from Mycobacterium tuberculosis (MVA85A) or recombinant hepatitis B virus surface antigen (rHBsAg) vaccines. The significant adjuvant activity observed provides good evidence supporting our hypothesis that CCR4 is a viable target for rational adjuvant design.
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Adjuvantes Imunológicos/farmacologia , Receptores CCR4/antagonistas & inibidores , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL17/metabolismo , Quimiocina CCL22/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Simulação por Computador , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Vacinas contra Hepatite B/administração & dosagem , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Conformação Proteica , Receptores CCR4/química , Receptores CCR4/metabolismo , Linfócitos T Reguladores/citologia , Vacinas contra a Tuberculose/administração & dosagemRESUMO
BACKGROUND: Cognitive impairment (CI) is one of the most feared and debilitating complications of PD. No therapy has been shown to slow or prevent CI in PD. OBJECTIVE: To determine associations between modifiable comorbidities, including cardiovascular disease risk factors, mood disorders, and sleep characteristics, and rate of cognitive decline in Parkinson's disease (PD). METHODS: Data from the Parkinson's Progression Markers Initiative (PPMI) cohort was queried for baseline cardiovascular disease risk factors, mood disorders, and sleep characteristics. Linear mixed- effects models (LME) were used to examine the association between baseline factors and change in cognition, evaluated by the Montreal Cognitive Assessment (MoCA) over time. Baseline comorbidities found to affect MoCA decline were assessed for an association with focal cognitive domains using LME. RESULTS: Higher Body Mass Index (BMI) (ß = -0.009, P = 0.039), State Trait Anxiety Inventory (STAI) (ß = -0.005, P < 0.001), Geriatric Depression Scale (GDS) (ß = -0.034, P < 0.001), Epworth Sleepiness Scale (ESS) (ß = -0.017, P = 0.003), and REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) (ß = -0.037, P < 0.001) were associated with faster rates of MoCA decline. Using established cut-offs for clinically significant symptoms, being overweight, or the presence of depression, excessive day time sleepiness (EDS), and possible REM sleep behavior disorder (pRBD), were all associated with faster rate of cognitive decline. CONCLUSION: Several modifiable baseline comorbidities are associated with faster rate of CI over time in patients with PD. These associations identify potential opportunities for early intervention that could influence CI in PD.
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Boosting bacillus Calmette-Guérin (BCG)-primed mice with a recombinant adenovirus expressing Mycobacterium tuberculosis Ag 85A by different administration routes has very different effects on protection against aerosol challenge with M. tuberculosis. Mice boosted intradermally make very strong splenic CD4 and CD8 Th1 cytokine responses to Ag 85A, but show no change in lung mycobacterial burden over BCG primed animals. In contrast, intranasally boosted mice show greatly reduced mycobacterial burden and make a much weaker splenic response but a very strong lung CD4 and CD8 response to Ag 85A and an increased response to purified protein derivative. This effect is associated with the presence in the lung of multifunctional T cells, with high median fluorescence intensity and integrated median fluorescence intensity for IFN-gamma, IL-2, and TNF. In contrast, mice immunized with BCG alone have few Ag-specific cells in the lung and a low proportion of multifunctional cells, although individual cells have high median fluorescence intensity. Successful immunization regimes appear to induce Ag-specific cells with abundant intracellular cytokine staining.
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Citocinas/biossíntese , Pulmão/imunologia , Mycobacterium tuberculosis/imunologia , Baço/imunologia , Células Th1/imunologia , Células Th1/microbiologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/prevenção & controle , Aciltransferases/administração & dosagem , Aciltransferases/imunologia , Adenovírus Humanos/genética , Adenovírus Humanos/imunologia , Administração Intranasal , Aerossóis , Sequência de Aminoácidos , Animais , Antígenos de Bactérias/administração & dosagem , Antígenos de Bactérias/imunologia , Vacina BCG/administração & dosagem , Vacina BCG/imunologia , Citocinas/fisiologia , Feminino , Humanos , Imunização Secundária/métodos , Injeções Intradérmicas , Pulmão/citologia , Pulmão/metabolismo , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Mycobacterium bovis/crescimento & desenvolvimento , Mycobacterium bovis/imunologia , Baço/citologia , Baço/metabolismo , Baço/microbiologia , Células Th1/metabolismo , Tuberculose Pulmonar/microbiologiaRESUMO
We report the results of an experiment on radio-tracking of individual grey field slugs in an arable field and associated data modelling designed to investigate the effect of slug population density in their movement. Slugs were collected in a commercial winter wheat field in which a 5x6 trapping grid had been established with 2m distance between traps. The slugs were taken to the laboratory, radio-tagged using a recently developed procedure, and following a recovery period released into the same field. Seventeen tagged slugs were released singly (sparse release) on the same grid node on which they had been caught. Eleven tagged slugs were released as a group (dense release). Each of the slugs was radio-tracked for approximately 10 h during which their position was recorded ten times. The tracking data were analysed using the Correlated Random Walk framework. The analysis revealed that all components of slug movement (mean speed, turning angles and movement/resting times) were significantly different between the two treatments. On average, the slugs released as a group disperse more slowly than slugs released individually and their turning angle has a clear anticlockwise bias. The results clearly suggest that population density is a factor regulating slug movement.
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Sistemas de Identificação Animal/métodos , Comportamento Animal/fisiologia , Gastrópodes/fisiologia , Locomoção/fisiologia , Movimento/fisiologia , Densidade Demográfica , Dispositivo de Identificação por Radiofrequência/métodos , Animais , TriticumRESUMO
BACKGROUND: The distribution of the grey field slug (Deroceras reticulatum Müller) in arable fields is characterised by patches containing higher slug densities dispersed within areas of lower densities. Behavioural responses that lead to the spatial/temporal stability of these patches are poorly understood, thus this study investigated behavioural mechanisms underpinning slug distribution using a new method for long-term tracking of individual slug movement in the field. RESULTS: A technique for implanting radio frequency identification (RFID) tags (each with a unique identification code) beneath the body wall of slugs was developed. Laboratory tests indicated no consistent detrimental effect on survival, feeding, egg laying or locomotor behaviour (velocity, distance travelled). Movement of individual slugs above and below the soil surface was recorded for >5 weeks (in spring and autumn) in winter wheat fields. Most (~80%) foraged within a limited area; and at the end of the observation period were located at a mean distance of 78.7 ± 33.7 cm (spring) or 101.9 ± 24.1 cm (autumn) from their release point. The maximum detected distance from the release point was 408.8 cm. The remaining slugs (~20%) moved further away and ultimately were lost. CONCLUSIONS: RFID tagging allowed continuous tracking of individual slugs, even below the soil surface. Localised movement of 80% of tracked slugs over 5 weeks offers a mechanism promoting stable slug patches in arable crops. Rapid dispersal of the remaining slugs facilitates exchange of individuals between patches. Precision targeting of pesticides at such stable slug patches may facilitate reduced usage. © 2020 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
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Gastrópodes , Animais , Produtos Agrícolas , Humanos , Estações do Ano , TriticumRESUMO
Exploitation of heterogenous distributions of Deroceras reticulatum, in arable fields by targeting molluscicide applications toward areas with higher slug densities, relies on these patches displaying sufficient spatio-temporal stability. Regular sampling of slug activity/distribution was undertaken using 1 ha rectangular grids of 100 refuge traps established in 22 commercial arable field crops. Activity varied significantly between the three years of the study, and the degree of aggregation (Taylor's Power Law) was higher in fields with higher mean trap catches. Hot spot analysis detected statistically significant spatial clusters in all fields, and in 162 of the 167 individual assessment visits. The five assessment visits in which no clusters were detected coincided with low slug activity (≤0.07 per trap). Generalized Linear Models showed significant spatial stability of patches in 11 fields, with non-significant fields also characterized by low slug activity (≤1.2 per trap). Mantel's permutation tests revealed a high degree of correlation between location of individual patches between sampling dates. It was concluded that patches of higher slug density were spatio-temporally stable, but detection using surface refuge traps (which rely on slug activity on the soil surface) was less reliable when adverse environmental conditions resulted in slugs retreating into the upper soil horizons.
RESUMO
In the light of the recent emergence of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis, the epidemic of tuberculosis (TB) in populations coinfected with human immunodeficiency virus, and the failure of Mycobacterium bovis bacillus Calmette-Guerin (BCG) to protect against disease, new vaccines against TB are urgently needed. Two promising new vaccine candidates are the recombinant DeltaureC hly(+) BCG (recBCG), which has been developed to replace the current BCG vaccine strain, and modified vaccinia virus Ankara (MVA) expressing M. tuberculosis antigen 85A (MVA85A), which is a leading candidate vaccine designed to boost the protective efficacy of BCG. In the present study, we examined the effect of MVA85A boosting on the protection afforded at 12 weeks postchallenge by BCG and recBCG by using bacterial CFU as an efficacy readout. recBCG-immunized mice were significantly better protected against aerosol challenge with M. tuberculosis than mice immunized with the parental strain of BCG. Intradermal boosting with MVA85A did not reduce the bacterial burden any further. In order to identify a marker for the development of a protective immune response against M. tuberculosis challenge, we analyzed splenocytes after priming or prime-boosting by using intracytoplasmic cytokine staining and assays for cytokine secretion. Boosting with MVA85A, but not priming with BCG or recBCG, greatly increased the antigen 85A-specific T-cell response, suggesting that the mechanism of protection may differ from that against BCG or recBCG. We show that the numbers of systemic multifunctional cytokine-producing cells did not correlate with protection against aerosol challenge in BALB/c mice. This emphasizes the need for new biomarkers for the evaluation of TB vaccine efficacy.