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Preschool childcare is considered an important policy for reducing inequalities in children's cognitive and socio-emotional development, although the population-level benefits for children under three years, is less clear. We examined the potential for childcare across the whole early years' period to benefit mental health and reduce inequalities, under different hypothetical policy scenarios, in the Growing Up in Scotland study. Marginal structural logistic regression models estimated odds ratios (ORs) to quantify inequalities in mental health and consider how these would be altered under different hypothetical scenarios. Mental health (the outcome) was measured using the total Strengths and Difficulties Questionnaire score at the start of primary school. Socioeconomic circumstances (the exposure) were represented by maternal educational measured in infancy. Sequence analysis identified common patterns of childcare usage from 10 months to four years (the mediator). Confounders were adjusted for using inverse probability of treatment weights and analyses accounted for sampling design and attrition (complete case sample, n = 3205). With virtually universal uptake of government-funded childcare at 3-4 years, most variation was seen before age three. Four groups were identified: 'Parents, family & friends' (35.8%), 'Grandparents' (32.7%), 'Private group childcare' (e.g. nurseries 23.5%), 'Single professional care' (e.g. childminders 8.1%). Children whose mothers had low, compared to high, educational qualifications were 3.18 times more likely to have mental health problems (95% CI: 1.88-5.37). In a hypothetical scenario where everyone received private group childcare, inequalities increased slightly to 3.78 (95%CI: 1.46-9.76). In an alternative scenario, where everyone received single professional childcare, inequalities in mental health reduced to 2.42 (95% CI: 0.20-28.76), albeit with wide confidence intervals. Universal childcare provision before three years may widen or narrow socioeconomic inequalities in children's mental health, depending on the childcare type provided. Further research is required to understand the role of childcare quality, which we were unable to account for.
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Host-parasite interactions exert strong selection pressures on the genomes of both host and parasite. These interactions can lead to negative frequency-dependent selection, a form of balancing selection that is hypothesised to explain the high levels of polymorphism seen in many host immune and parasite antigen loci. Here, we sequence the genomes of several individuals of Heligmosomoides bakeri, a model parasite of house mice, and Heligmosomoides polygyrus, a closely related parasite of wood mice. Although H. bakeri is commonly referred to as H. polygyrus in the literature, their genomes show levels of divergence that are consistent with at least a million years of independent evolution. The genomes of both species contain hyper-divergent haplotypes that are enriched for proteins that interact with the host immune response. Many of these haplotypes originated prior to the divergence between H. bakeri and H. polygyrus, suggesting that they have been maintained by long-term balancing selection. Together, our results suggest that the selection pressures exerted by the host immune response have played a key role in shaping patterns of genetic diversity in the genomes of parasitic nematodes.
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Nematospiroides dubius , Trichostrongyloidea , Ratones , Animales , Interacciones Huésped-Parásitos/fisiología , Nematospiroides dubius/genéticaRESUMEN
Importance: How population mental health has evolved across the COVID-19 pandemic under varied lockdown measures is poorly understood, and the consequences for health inequalities are unclear. Objective: To investigate changes in mental health and sociodemographic inequalities from before and across the first year of the COVID-19 pandemic in 11 longitudinal studies. Design, Setting, and Participants: This cohort study included adult participants from 11 UK longitudinal population-based studies with prepandemic measures of psychological distress. Analyses were coordinated across these studies, and estimates were pooled. Data were collected from 2006 to 2021. Exposures: Trends in the prevalence of poor mental health were assessed in the prepandemic period (time period 0 [TP 0]) and at 3 pandemic TPs: 1, initial lockdown (March to June 2020); 2, easing of restrictions (July to October 2020); and 3, a subsequent lockdown (November 2020 to March 2021). Analyses were stratified by sex, race and ethnicity, education, age, and UK country. Main Outcomes and Measures: Multilevel regression was used to examine changes in psychological distress from the prepandemic period across the first year of the COVID-19 pandemic. Psychological distress was assessed using the 12-item General Health Questionnaire, the Kessler 6, the 9-item Malaise Inventory, the Short Mood and Feelings Questionnaire, the 8-item or 9-item Patient Health Questionnaire, the Hospital Anxiety and Depression Scale, and the Centre for Epidemiological Studies-Depression across different studies. Results: In total, 49â¯993 adult participants (12â¯323 [24.6%] aged 55-64 years; 32â¯741 [61.2%] women; 4960 [8.7%] racial and ethnic minority) were analyzed. Across the 11 studies, mental health deteriorated from prepandemic scores across all 3 pandemic periods, but there was considerable heterogeneity across the study-specific estimated effect sizes (pooled estimate for TP 1: standardized mean difference [SMD], 0.15; 95% CI, 0.06-0.25; TP 2: SMD, 0.18; 95% CI, 0.09-0.27; TP 3: SMD, 0.21; 95% CI, 0.10-0.32). Changes in psychological distress across the pandemic were higher in women (TP 3: SMD, 0.23; 95% CI, 0.11, 0.35) than men (TP 3: SMD, 0.16; 95% CI, 0.06-0.26) and lower in individuals with below-degree level education at TP 3 (SMD, 0.18; 95% CI, 0.06-0.30) compared with those who held degrees (SMD, 0.26; 95% CI, 0.14-0.38). Increased psychological distress was most prominent among adults aged 25 to 34 years (SMD, 0.49; 95% CI, 0.14-0.84) and 35 to 44 years (SMD, 0.35; 95% CI, 0.10-0.60) compared with other age groups. No evidence of changes in distress differing by race and ethnicity or UK country were observed. Conclusions and Relevance: In this study, the substantial deterioration in mental health seen in the UK during the first lockdown did not reverse when lockdown lifted, and a sustained worsening was observed across the pandemic period. Mental health declines have been unequal across the population, with women, those with higher degrees, and those aged 25 to 44 years more affected than other groups.
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COVID-19 , Distrés Psicológico , Adulto , COVID-19/epidemiología , Estudios de Cohortes , Control de Enfermedades Transmisibles , Depresión/epidemiología , Etnicidad , Femenino , Humanos , Estudios Longitudinales , Masculino , Grupos Minoritarios , Pandemias , Reino Unido/epidemiologíaRESUMEN
To understand the contribution of mononuclear phagocytes (MNP), which include monocyte-derived intestinal macrophages, to the pathogenesis of inflammatory bowel disease (IBD), it is necessary to identify functionally-different MNP populations. We aimed to characterise intestinal macrophage populations in patients with IBD. We developed 12-parameter flow cytometry protocols to identify and human intestinal MNPs. We used these protocols to purify and characterize colonic macrophages from colonic tissue from patients with Crohn's disease (CD), ulcerative colitis (UC), or non-inflamed controls, in a cross-sectional study. We identify macrophage populations (CD45+CD64+ HLA-DR+) and describe two distinct subsets, differentiated by their expression of the mannose receptor, CD206. CD206+ macrophages expressed markers consistent with a mature phenotype: high levels of CD68 and CD163, higher transcription of IL-10 and lower expression of TREM1. CD206- macrophages appear to be less mature, with features more similar to their monocytic precursors. We identified and purified macrophage populations from human colon. These appear to be derived from a monocytic precursor with high CCR2 and low CD206 expression. As these cells mature, they acquire expression of IL-10, CD206, CD63, and CD168. Targeting the newly recruited monocyte-derived cells may represent a fruitful avenue to ameliorate chronic inflammation in IBD.
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Susceptibilidad a Enfermedades , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/metabolismo , Biomarcadores , Susceptibilidad a Enfermedades/inmunología , Perfilación de la Expresión Génica , Humanos , Inmunidad Innata , Inmunidad Mucosa , Inmunofenotipificación , Enfermedades Inflamatorias del Intestino/patología , Interleucina-10/genética , Interleucina-10/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Glicoproteínas de Membrana/genética , Receptores Inmunológicos/genética , TranscriptomaRESUMEN
Centre-based childcare may benefit pre-school children and alleviate inequalities in early childhood development, but evidence on socio-emotional and physical health outcomes is limited. Data were from the UK Millennium Cohort Study (n = 14,376). Inverse-probability weighting was used to estimate confounder-adjusted population-average effects of centre and non-centre-based childcare (compared to parental care only) between ages 26-31 months on (age 3): internalising and externalising symptoms, pro-social behaviour, independence, emotional dysregulation, vocabulary, school readiness, and body mass index. To assess impacts on inequalities, controlled direct effects of low parental education and lone parenthood on all outcomes were estimated under two hypothetical scenarios: 1) universal take-up of centre-based childcare; and 2) parental care only. On average, non-centre based childcare improved vocabulary and centre-based care improved school readiness, with little evidence of other benefits. However, socio-economic inequalities were observed for all outcomes and were attenuated in scenario 1 (universal take-up). For example, inequalities in externalising symptoms (according to low parental education) were reduced from a confounder-adjusted standard deviation difference of 7.8 (95% confidence intervals: 6.7-8.8), to 1.7 (0.6-2.7). Inequalities by parental education in scenario 2 (parental care only) were wider than in scenario 1 for externalising symptoms (at 3.4; 2.4-4.4), and for emotional dysregulation and school readiness. Inequalities by lone parenthood, which were smaller, fell in scenario 1, and fell further in scenario 2. Universal access to centre-based pre-school care may alleviate inequalities, while restricted access (e.g. during lockdown for a pandemic such as Covid-19) may widen some inequalities in socioemotional and cognitive development.
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Vaccine hesitancy could undermine efforts to control COVID-19. We investigated the prevalence of COVID-19 vaccine hesitancy in the UK and identified vaccine hesitant subgroups. The 'Understanding Society' COVID-19 survey asked participants (n = 12,035) their likelihood of vaccine uptake and reason for hesitancy. Cross-sectional analysis assessed vaccine hesitancy prevalence and logistic regression calculated odds ratios. Overall vaccine hesitancy was low (18% unlikely/very unlikely). Vaccine hesitancy was higher in women (21.0% vs 14.7%), younger age groups (26.5% in 16-24 year olds vs 4.5% in 75 + ) and those with lower education levels (18.6% no qualifications vs 13.2% degree qualified). Vaccine hesitancy was high in Black (71.8%) and Pakistani/Bangladeshi (42.3%) ethnic groups. Odds ratios for vaccine hesitancy were 13.42 (95% CI:6.86, 26.24) in Black and 2.54 (95% CI:1.19, 5.44) in Pakistani/Bangladeshi groups (compared to White British/Irish) and 3.54 (95% CI:2.06, 6.09) for people with no qualifications versus degree. Urgent action to address hesitancy is needed for some but not all ethnic minority groups.
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COVID-19 , Vacunas , Vacunas contra la COVID-19 , Estudios Transversales , Etnicidad , Femenino , Humanos , Estudios Longitudinales , Grupos Minoritarios , SARS-CoV-2 , Reino UnidoRESUMEN
Extracellular vesicles (EVs) have emerged as a ubiquitous component of helminth excretory-secretory products that can deliver parasite molecules to host cells to elicit immunomodulatory effects. RNAs are one type of cargo molecule that can underpin EV functions, hence there is extensive interest in characterising the RNAs that are present in EVs from different helminth species. Here we outline methods for identifying all of the small RNAs (sRNA) in helminth EVs and address how different methodologies may influence the sRNAs detected. We show that different EV purification methods introduce relatively little variation in the sRNAs that are detected, and that different RNA library preparation methods yielded larger differences. We compared the EV sRNAs in the gastrointestinal nematode Heligmosomoides bakeri with those in EVs from the distantly related gastrointestinal nematode Trichuris muris, and found that many of the sRNAs in both organisms derive from repetitive elements or intergenic regions. However, only in H. bakeri do these RNAs contain a 5' triphosphate, and Guanine (G) starting nucleotide, consistent with their biogenesis by RNA-dependent RNA polymerases (RdRPs). Distinct microRNA (miRNA) families are carried in EVs from each parasite, with H. bakeri EVs specific for miR-71, miR-49, miR-63, miR-259 and miR-240 gene families, and T. muris EVs specific for miR-1, miR-1822 and miR-252, and enriched for miR-59, miR-72 and miR-44 families, with the miR-9, miR-10, miR-80 and let-7 families abundant in both. We found a larger proportion of miRNA reads derive from the mouse host in T. muris EVs, compared with H. bakeri EVs. Our report underscores potential biases in the sRNAs sequenced based on library preparation methods, suggests specific nematode lineages have evolved distinct sRNA synthesis/export pathways, and highlights specific differences in EV miRNAs from H. bakeri and T. muris that may underpin functional adaptation to their host niches.
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Vesículas Extracelulares/metabolismo , MicroARNs , ARN de Helminto , ARN Interferente Pequeño , Trichuris/metabolismo , Animales , MicroARNs/aislamiento & purificación , MicroARNs/metabolismo , ARN de Helminto/aislamiento & purificación , ARN de Helminto/metabolismo , ARN Interferente Pequeño/aislamiento & purificación , ARN Interferente Pequeño/metabolismoRESUMEN
Extracellular RNA has been proposed to mediate communication between cells and organisms however relatively little is understood regarding how specific sequences are selected for export. Here, we describe a specific Argonaute protein (exWAGO) that is secreted in extracellular vesicles (EVs) released by the gastrointestinal nematode Heligmosomoides bakeri, at multiple copies per EV. Phylogenetic and gene expression analyses demonstrate exWAGO orthologues are highly conserved and abundantly expressed in related parasites but highly diverged in free-living genus Caenorhabditis. We show that the most abundant small RNAs released from the nematode parasite are not microRNAs as previously thought, but rather secondary small interfering RNAs (siRNAs) that are produced by RNA-dependent RNA Polymerases. The siRNAs that are released in EVs have distinct evolutionary properties compared to those resident in free-living or parasitic nematodes. Immunoprecipitation of exWAGO demonstrates that it specifically associates with siRNAs from transposons and newly evolved repetitive elements that are packaged in EVs and released into the host environment. Together this work demonstrates molecular and evolutionary selectivity in the small RNA sequences that are released in EVs into the host environment and identifies a novel Argonaute protein as the mediator of this.
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Proteínas Argonautas/genética , Evolución Molecular , Heligmosomatoidea/genética , ARN Interferente Pequeño/genética , Animales , Caenorhabditis elegans/genética , Heligmosomatoidea/patogenicidad , Humanos , FilogeniaRESUMEN
In the course of a structure based drug discovery program the known anticancer candidate marimastat was uncovered as a potent inhibitor of an enzyme in nematode cuticle biogenesis. It was shown to kill Caenorhabditis elegans, and the sheep parasites Haemonchus contortus and Teladorsagia circumcinta via an entirely novel nematode-specific pathway, specifically by inhibiting cuticle-remodelling enzymes that the parasites require for the developmentally essential moulting process. This discovery prompted an investigation of the compound's effect on Heligmosomoides polygyrus parasites in a mouse model of helminth infection. Mice were administered the drug via oral gavage daily from day of infection for a period of 2 wk. A second group received the drug via intra-peritoneal implantation of an osmotic minipump for 4 wk. Control groups were administered identical volumes of water by oral gavage in both cases. Counts of H. polygyrus faecal egg and larval load showed that marimastat effected a consistent and significant reduction in egg laying, and a consistent but minor reduction in adult worm load when administered every day, starting on the first day of infection. However, the drug failed to have any significant effect on egg counts or worm burdens when administered to mice with established infections. Therefore, marimastat does not appear to show promise as an anthelmintic in gastrointestinal nematode infections, although other metalloproteases such as batimastat may prove more effective.
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Recent studies have demonstrated that many parasites release extracellular vesicles (EVs), yet little is known about the specific interactions of EVs with immune cells or their functions during infection. We show that EVs secreted by the gastrointestinal nematode Heligmosomoides polygyrus are internalized by macrophages and modulate their activation. EV internalization causes downregulation of type 1 and type 2 immune-response-associated molecules (IL-6 and TNF, and Ym1 and RELMα) and inhibits expression of the IL-33 receptor subunit ST2. Co-incubation with EV antibodies abrogated suppression of alternative activation and was associated with increased co-localization of the EVs with lysosomes. Furthermore, mice vaccinated with EV-alum generated protective immunity against larval challenge, highlighting an important role in vivo. In contrast, ST2-deficient mice are highly susceptible to infection, and they are unable to clear parasites following EV vaccination. Hence, macrophage activation and the IL-33 pathway are targeted by H. polygyrus EVs, while neutralization of EV function facilitates parasite expulsion.
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Vesículas Extracelulares/metabolismo , Inmunidad , Activación de Macrófagos , Nematospiroides dubius/metabolismo , Parásitos/metabolismo , Vacunas/inmunología , Animales , Anticuerpos Antihelmínticos/inmunología , Formación de Anticuerpos/efectos de los fármacos , Células de la Médula Ósea/citología , Citocalasina D/farmacología , Vesículas Extracelulares/efectos de los fármacos , Inmunidad/efectos de los fármacos , Proteína 1 Similar al Receptor de Interleucina-1 , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Parásitos/efectos de los fármacos , Receptores de Interleucina/metabolismo , VacunaciónRESUMEN
BACKGROUND AND AIMS: Hiatus hernia (HH) is a key mediator of gastro-oesophageal reflux disease but little is known about its significance in the general population. We studied the structure and function of the gastro-oesophageal junction in healthy volunteers with and without HH. METHODS: We compared 15 volunteers with HH, detected by endoscopy or MRI scan, but without gastro-oesophageal reflux disease with 15 controls matched for age, gender and body weight. Jumbo biopsies were taken across the squamocolumnar junction (SCJ). High-resolution pH metry (12 sensors) and manometry (36 sensors) were performed upright and supine, before and after a meal. The SCJ was marked with an endoscopically placed clip and visualised fluoroscopically. RESULTS: Cardiac mucosa was longer in volunteers with HH (3.5 vs 2.5â mm, p=0.01). There was no excessive acid reflux 5â cm above the upper border of the lower oesophageal sphincter (LOS) in either group but those with HH had short segment reflux 11â mm above the pH transition point after the meal when supine (pH<4 for 5.5% vs 0.3% of time, p=0.01). The SCJ and pH transition point were proximally displaced within the gastro-oesophageal junction in those with HH versus controls (p<0.05). The pH transition point was proximal to the peak LOS pressure point in HH subjects but distal to it in controls after the meal (p<0.05). When supine, the postprandial pH transition point crossed the SCJ in those with HH (p=0.03). CONCLUSIONS: Healthy volunteers with HH have increased intrasphincteric reflux and lengthening of cardiac mucosa in the absence of traditional transsphincteric reflux.
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Cardias/diagnóstico por imagen , Esfínter Esofágico Inferior/diagnóstico por imagen , Unión Esofagogástrica/diagnóstico por imagen , Reflujo Gastroesofágico/etiología , Hernia Hiatal/complicaciones , Membrana Mucosa/diagnóstico por imagen , Adulto , Anciano , Biopsia , Cardias/patología , Estudios de Casos y Controles , Endoscopía Gastrointestinal , Esfínter Esofágico Inferior/patología , Unión Esofagogástrica/patología , Femenino , Fluoroscopía , Determinación de la Acidez Gástrica , Voluntarios Sanos , Humanos , Imagen por Resonancia Magnética , Masculino , Manometría , Persona de Mediana Edad , Membrana Mucosa/patologíaRESUMEN
Gastroesophageal reflux disease is one of the commonest chronic conditions in the western world and its prevalence is increasing worldwide. The discovery of the acid pocket explained the paradox of acid reflux occurring more frequently in the postprandial period despite intragastric acidity being low due to the buffering effect of the meal. The acid pocket was first described in 2001 when it was detected as an area of low pH immediately distal to the cardia using dual pH electrode pull-through studies 15 minutes after a meal. It was hypothesized that there was a local pocket of acid close to the gastroesophageal junction that escapes the buffering effect of the meal, and that this is the source of postprandial acidic reflux. The presence of the acid pocket has been confirmed in other studies using different techniques including high-resolution pHmetry, Bravo capsule, magnetic resonance imaging, and scintigraphy. This review aims to describe what we know about the acid pocket including its length, volume, fluid constituents, and its relationship to the lower esophageal sphincter and squamocolumnar junction. We will discuss the possible mechanisms that lead to the formation of the acid pocket and examine what differences exist in patients who suffer from acid reflux. Treatments for reflux disease that affect the acid pocket will also be discussed.
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Unión Esofagogástrica/metabolismo , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Reflujo Gastroesofágico/metabolismo , Animales , Tampones (Química) , Endoscopía Capsular , Monitorización del pH Esofágico , Unión Esofagogástrica/fisiopatología , Reflujo Gastroesofágico/diagnóstico , Reflujo Gastroesofágico/etiología , Reflujo Gastroesofágico/fisiopatología , Reflujo Gastroesofágico/terapia , Humanos , Concentración de Iones de Hidrógeno , Imagen por Resonancia Magnética , Periodo Posprandial , Valor Predictivo de las Pruebas , Cintigrafía , Factores de Riesgo , Resultado del TratamientoRESUMEN
Heligmosomoides polygyrus (formerly known as Nematospiroides dubius, and also referred to by some as H. bakeri) is a gastrointestinal helminth that employs multiple immunomodulatory mechanisms to establish chronic infection in mice and closely resembles prevalent human helminth infections. H. polygyrus has been studied extensively in the field of helminth-derived immune regulation and has been found to potently suppress experimental models of allergy and autoimmunity (both with active infection and isolated secreted products). The protocol described in this paper outlines management of the H. polygyrus life cycle for consistent production of L3 larvae, recovery of adult parasites, and collection of their excretory-secretory products (HES).
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Nematospiroides dubius/crecimiento & desarrollo , Nematospiroides dubius/metabolismo , Animales , Estadios del Ciclo de Vida , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBARESUMEN
INTRODUCTION: Recently, we showed that the length of cardiac mucosa in healthy volunteers correlated with age and obesity. We have now examined the immunohistological characteristics of this expanded cardia to determine whether it may be due to columnar metaplasia of the distal oesophagus. METHODS: We used the squamocolumnar junction (SCJ), antral and body biopsies from the 52 Helicobacter pylori-negative healthy volunteers who had participated in our earlier physiological study and did not have hiatus hernia, transsphincteric acid reflux, Barrett's oesophagus or intestinal metaplasia (IM) at cardia. The densities of inflammatory cells and reactive atypia were scored at squamous, cardiac and oxyntocardiac mucosa of SCJ, antrum and body. Slides were stained for caudal type homeobox 2 (CDX-2), villin, trefoil factor family 3 (TFF-3) and liver-intestine (LI)-cadherin, mucin MUC1, Muc-2 and Muc-5ac. In addition, biopsies from 15 Barrett's patients with/without IM were stained and scored as comparison. Immunohistological characteristics were correlated with parameters of obesity and high-resolution pH metry recording. RESULTS: Cardiac mucosa had a similar intensity of inflammatory infiltrate to non-IM Barrett's and greater than any of the other upper GI mucosae. The immunostaining pattern of cardiac mucosa most closely resembled non-IM Barrett's showing only slightly weaker CDX-2 immunostaining. In distal oesophageal squamous mucosa, expression of markers of columnar differentiation (TFF-3 and LI-cadherin) was apparent and these correlated with central obesity (correlation coefficient (CC)=0.604, p=0.001 and CC=0.462, p=0.002, respectively). In addition, expression of TFF-3 in distal oesophageal squamous mucosa correlated with proximal extension of gastric acidity within the region of the lower oesophageal sphincter (CC=-0.538, p=0.001). CONCLUSIONS: These findings are consistent with expansion of cardia in healthy volunteers occurring by squamo columnar metaplasia of distal oesophagus and aggravated by central obesity. This metaplastic origin of expanded cardia may be relevant to the substantial proportion of cardia adenocarcinomas unattributable to H. pylori or transsphincteric acid reflux.
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Cardias/patología , Unión Esofagogástrica/patología , Biopsia , Femenino , Voluntarios Sanos , Humanos , Inmunohistoquímica , Masculino , Metaplasia/complicaciones , Metaplasia/patología , Persona de Mediana Edad , Obesidad Abdominal/complicaciones , Índice de Severidad de la EnfermedadRESUMEN
The murine intestinal nematode Heligmosomoides polygyrus exerts multiple immunomodulatory effects in the host, including the suppression of allergic inflammation in mice sensitized to allergen presented with alum adjuvant. Similar suppression is attained by co-administration of H. polygyrus excretory/secretory products (HES) with the sensitizing dose of ovalbumin (OVA) in alum. We investigated the mechanism of suppression by HES in this model, and found it was maintained in MyD88xTRIF-deficient mice, implying no role for helminth- or host-derived TLR ligands, or IL-1 family cytokines that signal in a MyD88- or TRIF-dependent manner. We also found suppression was unchanged in µMT mice, which lack B2 B cells, and that suppression was not abrogated when regulatory T cells were depleted in Foxp3.LuciDTR-4 mice. However, reduced IL-5 production was seen in the first 12 h after injection of OVA-alum when HES was co-administered, associated with reduced activation of IL-5(+) and IL-13(+) group 2 innate lymphoid cells. Thus, the suppressive effects of HES on alum-mediated OVA sensitization are reflected in the very earliest innate response to allergen exposure in vivo.
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Hipersensibilidad/inmunología , Linfocitos/inmunología , Nematospiroides dubius/inmunología , Proteínas Adaptadoras del Transporte Vesicular/deficiencia , Proteínas Adaptadoras del Transporte Vesicular/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Compuestos de Alumbre/administración & dosificación , Animales , Linfocitos B Reguladores/inmunología , Síndromes de Inmunodeficiencia/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ovalbúmina/administración & dosificación , Enfermedades de Inmunodeficiencia Primaria , Transducción de Señal/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
Over 25% of the world's population are infected with helminth parasites, the majority of which colonise the gastrointestinal tract. However, no vaccine is yet available for human use, and mechanisms of protective immunity remain unclear. In the mouse model of Heligmosomoides polygyrus infection, vaccination with excretory-secretory (HES) antigens from adult parasites elicits sterilising immunity. Notably, three purified HES antigens (VAL-1, -2 and -3) are sufficient for effective vaccination. Protection is fully dependent upon specific IgG1 antibodies, but passive transfer confers only partial immunity to infection, indicating that cellular components are also required. Moreover, immune mice show greater cellular infiltration associated with trapping of larvae in the gut wall prior to their maturation. Intra-vital imaging of infected intestinal tissue revealed a four-fold increase in extravasation by LysM+GFP+ myeloid cells in vaccinated mice, and the massing of these cells around immature larvae. Mice deficient in FcRγ chain or C3 complement component remain fully immune, suggesting that in the presence of antibodies that directly neutralise parasite molecules, the myeloid compartment may attack larvae more quickly and effectively. Immunity to challenge infection was compromised in IL-4Rα- and IL-25-deficient mice, despite levels of specific antibody comparable to immune wild-type controls, while deficiencies in basophils, eosinophils or mast cells or CCR2-dependent inflammatory monocytes did not diminish immunity. Finally, we identify a suite of previously uncharacterised heat-labile vaccine antigens with homologs in human and veterinary parasites that together promote full immunity. Taken together, these data indicate that vaccine-induced immunity to intestinal helminths involves IgG1 antibodies directed against secreted proteins acting in concert with IL-25-dependent Type 2 myeloid effector populations.
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Anticuerpos Antihelmínticos/inmunología , Antígenos Helmínticos/inmunología , Inmunoglobulina G/inmunología , Interleucina-4/inmunología , Interleucinas/inmunología , Nematospiroides dubius/inmunología , Infecciones por Strongylida/inmunología , Vacunación , Animales , Anticuerpos Antihelmínticos/genética , Humanos , Inmunoglobulina G/genética , Interleucina-4/genética , Interleucinas/genética , Larva/inmunología , Ratones , Ratones Noqueados , Infecciones por Strongylida/genética , Infecciones por Strongylida/prevención & controlRESUMEN
OBJECTIVE: There is a high incidence of inflammation and metaplasia at the gastro-oesophageal junction (GOJ) in asymptomatic volunteers. Additionally, the majority of patients with GOJ adenocarcinomas have no history of reflux symptoms. We report the effects of waist belt and increased waist circumference (WC) on the physiology of the GOJ in asymptomatic volunteers. DESIGN: 12 subjects with normal and 12 with increased WC, matched for age and gender were examined fasted and following a meal and with waist belts on and off. A magnet was clipped to the squamo-columnar junction (SCJ). Combined assembly of magnet-locator probe, 12-channel pH catheter and 36-channel manometer was passed. RESULTS: The waist belt and increased WC were each associated with proximal displacement of SCJ within the diaphragmatic hiatus (relative to upper border of lower oesophageal sphincter (LOS), peak LOS pressure point and pressure inversion point, and PIP (all p<0.05). The magnitude of proximal migration of SCJ during transient LOS relaxations was reduced by 1.6-2.6â cm with belt on versus off (p=0.01) and in obese versus non-obese (p=0.04), consistent with its resting position being already proximally displaced. The waist belt, but not increased WC, was associated with increased LOS pressure (vs intragastric pressure) and movement of pH transition point closer to SCJ. At 5â cm above upper border LOS, the mean % time pH <4 was <4% in all studied groups. Acid exposure 0.5-1.5â cm above SCJ was increased, with versus without, belt (p=0.02) and was most marked in obese subjects with belt. CONCLUSIONS: Our findings indicate that in asymptomatic volunteers, waist belt and central obesity cause partial hiatus herniation and short-segment acid reflux. This provides a plausible explanation for the high incidence of inflammation and metaplasia and occurrence of neoplasia at the GOJ in subjects without a history of reflux symptoms.
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Vestuario/efectos adversos , Reflujo Gastroesofágico/etiología , Hernia Hiatal/etiología , Obesidad Abdominal/fisiopatología , Presión/efectos adversos , Adulto , Enfermedades Asintomáticas , Estudios de Casos y Controles , Monitorización del pH Esofágico , Femenino , Reflujo Gastroesofágico/diagnóstico , Hernia Hiatal/diagnóstico , Humanos , Masculino , Manometría , Circunferencia de la CinturaRESUMEN
BACKGROUND & AIMS: In the West, a substantial proportion of subjects with adenocarcinoma of the gastric cardia and gastroesophageal junction have no history of reflux. We studied the gastroesophageal junction in asymptomatic volunteers with normal and large waist circumferences (WCs) to determine if central obesity is associated with abnormalities that might predispose individuals to adenocarcinoma. METHODS: We performed a study of 24 healthy, Helicobacter pylori-negative volunteers with a small WC and 27 with a large WC. Abdominal fat was quantified by magnetic resonance imaging. Jumbo biopsy specimens were taken across the squamocolumnar junction (SCJ). High-resolution pH-metry (12 sensors) and manometry (36 sensors) were performed in upright and supine subjects before and after a meal; the SCJ was visualized fluoroscopically. RESULTS: The cardiac mucosa was significantly longer in the large WC group (2.5 vs 1.75 mm; P = .008); its length correlated with intra-abdominal (R = 0.35; P = .045) and total abdominal (R = 0.37; P = .034) fat. The SCJ was closer to the upper border of the lower esophageal sphincter (LES) in subjects with a large WC (2.77 vs 3.54 cm; P = .02). There was no evidence of excessive reflux 5 cm above the LES in either group. Gastric acidity extended more proximally within the LES in the large WC group, compared with the upper border (2.65 vs 4.1 cm; P = .027) and peak LES pressure (0.1 cm proximal vs 2.1 cm distal; P = .007). The large WC group had shortening of the LES, attributable to loss of the distal component (total LES length, 3 vs 4.5 cm; P = .043). CONCLUSIONS: Central obesity is associated with intrasphincteric extension of gastric acid and cardiac mucosal lengthening. The latter might arise through metaplasia of the most distal esophageal squamous epithelium and this process might predispose individuals to adenocarcinoma.
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Cardias/patología , Reflujo Gastroesofágico/etiología , Obesidad/complicaciones , Circunferencia de la Cintura , Adulto , Anciano , Biopsia , Esfínter Esofágico Inferior/patología , Femenino , Determinación de la Acidez Gástrica , Humanos , Masculino , Manometría , Metaplasia , Persona de Mediana Edad , Membrana Mucosa/patología , Obesidad/patologíaRESUMEN
Understanding the physiology of gastroesophageal junction (GEJ) is important as failure of its function is associated with reflux disease, hiatus hernia, and cancer. In recent years, there have been impressive developments in high resolution technologies allowing measurement of luminal pressure, pH, and impedance. One obvious deficiency is the lack of technique to monitor the movement and location of the GEJ over a prolonged period of time. Proximal movement of the GEJ during peristalsis and transient lower esophageal sphincter relaxations (TLESRs) is due to shortening of the longitudinal muscle of the esophagus. Techniques for measuring shortening include fluoroscopic imaging of mucosal clip, high-frequency intraluminal ultrasound, and high resolution manometry, but these techniques have limitations. Short segment reflux is recently found to be more common than traditional reflux and may account for the high prevalence of intestinal metaplasia and cancer seen at GEJ. While high resolution pHmetry is available, there is no technique that can reliably and continuously measure the position of the squamocolumnar junction. A new technique is recently reported allowing a precise and continuous measurement of the GEJ based on the principle of Hall effect. Reported studies have validated its accuracy both on the bench and against the gold standard, fluoroscopy. It has been used alongside high resolution manometry in studying the behavior of the GEJ during TLESRs and swallows. While there are challenges associated with this new technique, there are promising ongoing developments. There is exciting time ahead in research and clinical applications for this new technique.
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Unión Esofagogástrica/fisiología , Composición Corporal , Impedancia Eléctrica , Unión Esofagogástrica/patología , Unión Esofagogástrica/fisiopatología , Fluoroscopía/métodos , Reflujo Gastroesofágico/fisiopatología , Hernia Hiatal/fisiopatología , Humanos , Concentración de Iones de Hidrógeno , Manometría , Monitoreo Fisiológico , Neoplasias/fisiopatología , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: Acid reflux produces troublesome symptoms (heartburn) and complications including esophagitis, Barrett's esophagus, and adenocarcinoma. Reflux occurs due to excessive and inappropriate relaxation of the lower esophageal sphincter. An important mediator of this is nitric oxide, high concentrations of which are generated within the lumen when swallowed saliva meets gastric acid. Saliva contains nitrite, derived from the enterosalivary recirculation of dietary nitrate, which is reduced to nitric oxide by gastric acid. The aim of this study was to investigate whether salivary nitrite contributes to dysfunction of the lower esophageal sphincter. MATERIALS AND METHODS: In 20 volunteers, studies of gastro-esophageal function were performed on four separate days, following consumption of a standardized meal, with saliva nitrite concentrations modified differently each day by intra-oral nitrite infusion. RESULTS: The infusions produced an appropriate range in saliva nitrite concentrations, from below to well above the physiological range. The standardized meal induced expected physiological changes in gastro-esophageal function confirming the recordings were sensitive and robust. Esophageal acid exposure (primary outcome) was similar on each study day. Secondary outcomes, including number and duration of reflux events, rate of transient lower esophageal sphincter relaxations, lower esophageal sphincter pressure and rate of gastric emptying were also unaffected by variations in saliva nitrite concentration. CONCLUSIONS: Nitrite in swallowed saliva does not modify gastro-esophageal junction function or predispose to gastro-esophageal reflux. The wide range in saliva nitrite concentrations, the sensitivity of the physiological recordings and the number of subjects studied make it very unlikely that an effect has been missed.