Tesis doctoral inédita leída en la Universidad Autónoma de Madrid. Facultad de Medicina, Departamento de Pediatría. Fecha de lectura: 15 de Diciembre de 2011
Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we ...perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P<5 × 10
), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts.
The circadian clock regulates multiple aspects of human physiology including immunity. People have a circadian preference termed chronotype. Those with an evening preference may be better suited to ...shift work, but also carry higher risk of adverse health. Shift work leads to misalignment of circadian rhythms and is associated with increased risk of inflammatory disease such as asthma and cancer. Here, we investigate the association between chronotype, shift work, and rheumatoid arthritis (RA). The associations between exposures of shift work and chronotype on risk of RA were studied in up to 444,210 U.K. Biobank participants. Multivariable logistic regression models were adjusted for covariates: age, sex, ethnicity, alcohol intake, smoking history, Townsend Deprivation Index (TDI), sleep duration, length of working week, and body mass index (BMI). After adjusting for covariates, individuals with a morning chronotype had lower odds of having rheumatoid arthritis (RA; odds ratio OR: 0.93, 95% confidence interval CI: 0.88-0.99) when compared to intermediate chronotypes. The association between morning chronotype and RA persisted with a more stringent RA case definition (covariate-adjusted OR: 0.89, 95% CI: 0.81-0.97). When adjusted for age, sex, ethnicity, and TDI, shift workers had higher odds of RA (OR: 1.22, 95% CI: 1.1-1.36) compared to day workers that attenuated to the null after further covariate adjustment (OR: 1.1, 95% CI: 0.98-1.22). Morning chronotypes working permanent night shifts had significantly higher odds of RA compared to day workers (OR: 1.89, 95% CI: 1.19-2.99). These data point to a role for circadian rhythms in RA pathogenesis. Further studies are required to determine the mechanisms underlying this association and understand the potential impact of shift work on chronic inflammatory disease and its mediating factors.
Currently, licensed seasonal influenza vaccines display variable vaccine effectiveness, and there remains a need for novel vaccine platforms capable of inducing broader responses against viral ...protein domains conserved among influenza subtypes. We conducted a first-in-human, randomized, open-label, phase 1 clinical trial ( NCT03186781 ) to evaluate a novel ferritin (H2HA-Ferritin) nanoparticle influenza vaccine platform. The H2 subtype has not circulated in humans since 1968. Adults born after 1968 have been exposed to only the H1 subtype of group 1 influenza viruses, which shares a conserved stem with H2. Including both H2-naive and H2-exposed adults in the trial allowed us to evaluate memory responses against the conserved stem domain in the presence or absence of pre-existing responses against the immunodominant HA head domain. Fifty healthy participants 18-70 years of age received H2HA-Ferritin intramuscularly as a single 20-μg dose (n = 5) or a 60-μg dose either twice in a homologous (n = 25) prime-boost regimen or once in a heterologous (n = 20) prime-boost regimen after a matched H2 DNA vaccine prime. The primary objective of this trial was to evaluate the safety and tolerability of H2HA-Ferritin either alone or in prime-boost regimens. The secondary objective was to evaluate antibody responses after vaccination. Both vaccines were safe and well tolerated, with the most common solicited symptom being mild headache after both H2HA-Ferritin (n = 15, 22%) and H2 DNA (n = 5, 25%). Exploratory analyses identified neutralizing antibody responses elicited by the H2HA-Ferritin vaccine in both H2-naive and H2-exposed populations. Furthermore, broadly neutralizing antibody responses against group 1 influenza viruses, including both seasonal H1 and avian H5 subtypes, were induced in the H2-naive population through targeting the HA stem. This ferritin nanoparticle vaccine technology represents a novel, safe and immunogenic platform with potential application for pandemic preparedness and universal influenza vaccine development.
Ebola virus infection is a highly lethal disease for which there are no effective therapeutic or preventive treatments. Several vaccines have provided immune protection in laboratory animals, but ...because outbreaks occur unpredictably and sporadically, vaccine efficacy cannot be proven in human trials, which is required for traditional regulatory approval. The Food and Drug Administration has introduced the 'animal rule', to allow laboratory animal data to be used to show efficacy when human trials are not logistically feasible. In this Review, we describe immune correlates of vaccine protection against Ebola virus in animals. This research provides a basis for bridging the gap from basic research to human vaccine responses in support of the licensing of vaccines through the animal rule.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
RATIONALE:Circulating glycoprotein N-acetyl glucosamine residues have recently been associated with incident cardiovascular disease and diabetes mellitus.
OBJECTIVE:Using a plasma glycan biosignature ...(GlycA) to identify circulating N-acetyl glycan groups, we examined the longitudinal association between GlycA and mortality among initially healthy individuals.
METHODS AND RESULTS:We quantified GlycA by 400 MHz H nuclear magnetic resonance spectroscopy in 27 524 participants in the Women’s Health Study (NCT00000479). The primary outcome was all-cause mortality. We replicated the findings in an independent cohort of 12 527 individuals in the Justification for the Use of statins in Preventionan Intervention Trial Evaluating Rosuvastatin (JUPITER) trial (NCT00239681). We also undertook secondary examination of cardiovascular disease and cancer mortality in the Women’s Health Study. In the Women’s Health Study, during 524 515 person-years of follow-up (median, 20.5 years), there were 3523 deaths. Risk factor–adjusted multivariable Cox proportional hazard ratio (95% confidence interval) per SD increment in GlycA for all-cause mortality was significantly increased at 5 years (1.21 1.06–1.40) and during maximal follow-up (1.14 1.09–1.16). Similar risk for all-cause mortality was observed in the replication cohort (1.33 1.21–1.45). In the Women’s Health Study, risk of cardiovascular disease mortality was increased at 5 years (1.43 1.05–1.95) and during maximal follow-up (1.15 1.04–1.26) and of cancer mortality at 5 years (1.23 1.02–1.47) and during maximal follow-up (1.08 1.01–1.16). Examination of correlations and mortality associations adjusted for high-sensitivity C-reactive protein, fibrinogen, and intercellular adhesion molecule-1, suggested that GlycA reflects summative risk related to multiple pathways of systemic inflammation.
CONCLUSIONS:Among initially healthy individuals, elevated baseline circulating glycoprotein N-acetyl methyl groups were associated with longitudinal risk of all-cause, cardiovascular, and cancer mortality.
Predictable and sustainable engraftment of live biotherapeutic products into the human gut microbiome is being explored as a promising way to modulate the human gut microbiome. We utilize a synbiotic ...approach pairing the infant gut microbe Bifidobacterium longum subspecies infantis (B. infantis) and human milk oligosaccharides (HMO). B. infantis, which is typically absent in adults, engrafts into healthy adult microbiomes in an HMO-dependent manner at a relative abundance of up to 25% of the bacterial population without antibiotic pretreatment or adverse effects. Corresponding changes in metabolites are detected. Germ-free mice transplanted with dysbiotic human microbiomes also successfully engraft with B. infantis in an HMO-dependent manner, and the synbiotic augments butyrate levels both in this in vivo model and in in vitro cocultures of the synbiotic with specific Firmicutes species. Finally, the synbiotic inhibits the growth of enteropathogens in vitro. Our findings point to a potential safe mechanism for ameliorating dysbioses characteristic of numerous human diseases.
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•Co-dosing with HMO enables reversible gut engraftment of B. infantis in healthy adults•The synbiotic is safe and does not require the use of antibiotics for gut engraftment•Synbiotic induces butyrate production in mice colonized with dysbiotic human microbiota•In vivo and in vitro models show beneficial impacts on metabolites and enteropathogens
Button et al. present proof-of-concept data showing that Bifidobacterium infantis, an infant gut microbe, can be reversibly introduced and maintained in healthy adult guts without prior antibiotic treatment if human milk oligosaccharides are provided. Higher colonization levels are achieved in dysbiotic human-microbiota-associated mice with concomitant butyrate production, suggesting therapeutic potential.
Abstract Behavioral scientists have increasingly included inflammatory biology as mechanisms in their investigation of psychosocial dynamics on the pathobiology of disease. However, a lack of ...standardization of inclusion and exclusion criteria and assessment of relevant control variables impacts the interpretation of these studies. The present paper reviews and discusses human biobehavioral factors that can affect the measurement of circulating markers of inflammation. Keywords relevant to inflammatory biology and biobehavioral factors were searched through PubMed. Age, sex, and hormonal status, socioeconomic status, ethnicity and race, body mass index, exercise, diet, caffeine, smoking, alcohol, sleep disruption, antidepressants, aspirin, and medications for cardiovascular disease are all reviewed. A tiered set of recommendations as to whether each variable should be assessed, controlled for, or used as an exclusion criteria is provided. These recommendations provide a framework for observational and intervention studies investigating linkages between psychosocial and behavioral factors and inflammation.
How do large and small animals defend against parasite challenges given the consequences of body mass on physiology and disease transmission? Functionally equivalent mammalian and avian granulocytes ...increased disproportionately with mass (i.e., hypermetrically), such that large organisms have higher concentrations than expected by mass alone. However, how ectothermic leucocyte concentrations scale is understudied. We hypothesized that differences exist in the scaling of leucocyte concentrations between endotherms and ectotherms as these groups have substantial differences in their physiology and immunology. Analysis was conducted using MCMCglmm, phylogenetically informed models to determine which existing scaling hypothesis best predicted relationships between mass and lymphocyte and heterophil concentrations among >120 species of reptiles and compared our results with those from birds and mammals. We also compared body mass and life history as a predictor of variation in immune cell concentrations. Reptilian lymphocyte concentrations scaled close to isometrically (i.e., mass‐invariant; phylogenetic MCMCglmm: b(mean, 95% CI) = ‐0.040, ‐0.072, ‐0.007), and the slope was indistinguishable from the slope found for mammals and birds. In contrast, reptilian heterophil concentrations scaled isometrically (b =0.006, ‐0.028, 0.040), whereas functionally equivalent mammalian and avian granulocytes scaled hypermetrically. Although reptilian leucocytes were mass‐invariant, the slope was greater than predicted if metabolic rate serves as a pace marker for immune defenses, suggesting that large organisms have greater protection than expected by the Rate of Metabolism Hypothesis. Life history was also a poor predictor of variation in reptilian heterophil and lymphocyte concentrations. Our results provide novel insight into large scale patterns of immune defenses of endothermic and ectothermic vertebrates and have direct implications for modeling the evolution of immune defenses and identifying parasite reservoirs.
The authors sought to prospectively determine the safety and efficacy of next-day discharge using the Vancouver 3M (Multidisciplinary, Multimodality, but Minimalist) Clinical Pathway.
Transfemoral ...transcatheter aortic valve replacement (TAVR) is an alternative to surgery in high- and intermediate-risk patients; however, hospital stays average at least 6 days in most trials. The Vancouver 3M Clinical Pathway is focused on next-day discharge, made possible by the use of objective screening criteria as well as streamlined peri- and post-procedural management guidelines.
Patients were enrolled from 6 low-volume (<100 TAVR/year), 4 medium-volume, and 3 high-volume (>200 TAVR/year) centers in Canada and the United States. The primary outcomes were a composite of all-cause death or stroke by 30 days and the proportion of patients successfully discharged home the day following TAVR.
Of 1,400 screened patients, 411 were enrolled at 13 centers and received a SAPIEN XT (58.2%) or SAPIEN 3 (41.8%) valve (Edwards Lifesciences, Irvine, California). In centers enrolling exclusively in the study, 55% of screened patients were enrolled. The median age was 84 years (interquartile range: 78 to 87 years) with a median STS score of 4.9% (interquartile range: 3.3% to 6.8%). Next-day discharge home was achieved in 80.1% of patients, and within 48 h in 89.5%. The composite of all-cause mortality or stroke by 30 days occurred in 2.9% (95% confidence interval: 1.7% to 5.1%), with neither component of the primary outcome affected by hospital TAVR volume (p = 0.51). Secondary outcomes at 30 days included major vascular complication 2.4% (n = 10), readmission 9.2% (n = 36), cardiac readmission 5.7% (n = 22), new permanent pacemaker 5.7% (n = 23), and >mild paravalvular regurgitation 3.8% (n = 15).
Adherence to the Vancouver 3M Clinical Pathway at low-, medium-, and high-volume TAVR centers allows next-day discharge home with excellent safety and efficacy outcomes.
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