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Low-toxicity InP-based quantum dots (QDs) exhibit potential for replacing Cd/Pb-containing QDs in the visible and near-infrared regions. Despite advancements, further improvement relies on synthesizing homogeneous InP QDs to achieve a high color purity. In a commonly employed two-step "seed-mediated" synthetic approach, we demonstrate the high sensitivity of InP seed sizes and size distribution to the quantities of trioctylphosphine (TOP) and tris(trimethylsilyl)phosphine [(TMS)3P], attributed to the process of "self-focusing of size distribution" and enhanced reactivity of In-oleate through coordination with TOP. During growth, the processes of size focusing and defocusing are modulated by the accumulation of oleic acid and TOP molecules, as well as the amount of (TMS)3P in the growth precursor, which may relate to the dissolution process of InP magic size clusters. Through precise control, the best valley/depth ratio of InP QDs was 0.52 at the first absorption peak at 571 nm, resulting in luminescence with a full width at half-maximum of 35 at 620 nm with an absolute photoluminescence quantum yield around 90% after heteroepitaxial growth with ZnSe and ZnS shells.
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OBJECTIVE: IBD therapies and treatments are evolving to deeper levels of remission. Molecular measures of disease may augment current endpoints including the potential for less invasive assessments. DESIGN: Transcriptome analysis on 712 endoscopically defined inflamed (Inf) and 1778 non-inflamed (Non-Inf) intestinal biopsies (n=498 Crohn's disease, n=421 UC and 243 controls) in the Mount Sinai Crohn's and Colitis Registry were used to identify genes differentially expressed between Inf and Non-Inf biopsies and to generate a molecular inflammation score (bMIS) via gene set variance analysis. A circulating MIS (cirMIS) score, reflecting intestinal molecular inflammation, was generated using blood transcriptome data. bMIS/cirMIS was validated as indicators of intestinal inflammation in four independent IBD cohorts. RESULTS: bMIS/cirMIS was strongly associated with clinical, endoscopic and histological disease activity indices. Patients with the same histologic score of inflammation had variable bMIS scores, indicating that bMIS describes a deeper range of inflammation. In available clinical trial data sets, both scores were responsive to IBD treatment. Despite similar baseline endoscopic and histologic activity, UC patients with lower baseline bMIS levels were more likely treatment responders compared with those with higher levels. Finally, among patients with UC in endoscopic and histologic remission, those with lower bMIS levels were less likely to have a disease flare over time. CONCLUSION: Transcriptionally based scores provide an alternative objective and deeper quantification of intestinal inflammation, which could augment current clinical assessments used for disease monitoring and have potential for predicting therapeutic response and patients at higher risk of disease flares.
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Colite Ulcerativa , Doença de Crohn , Humanos , Colite Ulcerativa/patologia , Inflamação/genética , Inflamação/patologia , Doença de Crohn/patologia , Biópsia , Biomarcadores , Mucosa Intestinal/patologiaRESUMO
BACKGROUND & AIMS: Polygenic and environmental factors are underlying causes of inflammatory bowel disease (IBD). We hypothesized that integration of the genetic loci controlling a metabolite's abundance, with known IBD genetic susceptibility loci, may help resolve metabolic drivers of IBD. METHODS: We measured the levels of 1300 metabolites in the serum of 484 patients with ulcerative colitis (UC) and 464 patients with Crohn's disease (CD) and 365 controls. Differential metabolite abundance was determined for disease status, subtype, clinical and endoscopic disease activity, as well as IBD phenotype including disease behavior, location, and extent. To inform on the genetic basis underlying metabolic diversity, we integrated metabolite and genomic data. Genetic colocalization and Mendelian randomization analyses were performed using known IBD risk loci to explore whether any metabolite was causally associated with IBD. RESULTS: We found 173 genetically controlled metabolites (metabolite quantitative trait loci, 9 novel) within 63 non-overlapping loci (7 novel). Furthermore, several metabolites significantly associated with IBD disease status and activity as defined using clinical and endoscopic indexes. This constitutes a resource for biomarker discovery and IBD biology insights. Using this resource, we show that a novel metabolite quantitative trait locus for serum butyrate levels containing ACADS was not supported as causal for IBD; replicate the association of serum omega-6 containing lipids with the fatty acid desaturase 1/2 locus and identify these metabolites as causal for CD through Mendelian randomization; and validate a novel association of serum plasmalogen and TMEM229B, which was predicted as causal for CD. CONCLUSIONS: An exploratory analysis combining genetics and unbiased serum metabolome surveys can reveal novel biomarkers of disease activity and potential mediators of pathology in IBD.
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Acil-CoA Desidrogenase/genética , Colite Ulcerativa/genética , Colite Ulcerativa/metabolismo , Doença de Crohn/genética , Doença de Crohn/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Butiratos/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Colite Ulcerativa/sangue , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/sangue , Doença de Crohn/tratamento farmacológico , Estudos Transversais , Fezes/química , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Células HEK293 , Humanos , Masculino , Análise da Randomização Mendeliana , Metaboloma , Pessoa de Meia-Idade , Plasmalogênios/sangue , Plasmalogênios/genética , Locos de Características Quantitativas , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND AND AIMS: Disease extent varies in ulcerative colitis (UC) from proctitis to left-sided colitis to pancolitis and is a major prognostic factor. When the extent of UC is limited there is often a sharp demarcation between macroscopically involved and uninvolved areas and what defines this or subsequent extension is unknown. We characterized the demarcation site molecularly and determined genes associated with subsequent disease extension. METHODS: We performed RNA sequence analysis of biopsy specimens from UC patients with endoscopically and histologically confirmed limited disease, of which a subset later extended. Biopsy specimens were obtained from the endoscopically inflamed upper (proximal) limit of disease, immediately adjacent to the uninvolved colon, as well as at more proximal, endoscopically uninflamed colonic segments. RESULTS: Differentially expressed genes were identified in the endoscopically inflamed biopsy specimens taken at each patient's most proximal diseased site relative to healthy controls. Expression of these genes in the more proximal biopsy specimens transitioned back to control levels abruptly or gradually, the latter pattern supporting the concept that disease exists beyond the endoscopic disease demarcation site. The gradually transitioning genes were associated with inflammation, angiogenesis, glucuronidation, and homeodomain pathways. A subset of these genes in inflamed biopsy specimens was found to predict disease extension better than clinical features and were responsive to biologic therapies. Network analysis revealed critical roles for interferon signaling in UC inflammation and poly(ADP-ribose) polymerase 14 (PARP14) was a predicted key driver gene of extension. Higher PARP14 protein levels were found in inflamed biopsy specimens of patients with limited UC that subsequently extended. CONCLUSION: Molecular predictors of disease extension reveal novel strategies for disease prognostication and potential therapeutic targeting.
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Colite Ulcerativa/genética , Colo/metabolismo , Perfilação da Expressão Gênica , Poli(ADP-Ribose) Polimerases/genética , Análise de Sequência de RNA , Transcriptoma , Teorema de Bayes , Biópsia , Estudos de Casos e Controles , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/patologia , Estudos Transversais , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Gravidade do Paciente , Poli(ADP-Ribose) Polimerases/metabolismo , Valor Preditivo dos Testes , Transdução de SinaisRESUMO
BACKGROUND: Wearable devices enable monitoring and measurement of physiological parameters over a 24-h period, and some of which exhibit circadian rhythm characteristics. However, the currently available R package cosinor could only analyze daily cross-sectional data and compare the parameters between groups with two levels. To evaluate longitudinal changes in the circadian patterns, we need to extend the model to a mixed-effect model framework, allowing for random effects and interaction between COSINOR parameters and time-varying covariates. RESULTS: We developed the cosinoRmixedeffects R package for modelling longitudinal periodic data using mixed-effects cosinor models. The model allows for covariates and interactions with the non-linear parameters MESOR, amplitude, and acrophase. To facilitate ease of use, the package utilizes the syntax and functions of the widely used emmeans package to obtain estimated marginal means and contrasts. Estimation and hypothesis testing involving the non-linear circadian parameters are carried out using bootstrapping. We illustrate the package functionality by modelling daily measurements of heart rate variability (HRV) collected among health care workers over several months. Differences in circadian patterns of HRV between genders, BMI, and during infection with SARS-CoV2 are evaluated to illustrate how to perform hypothesis testing. CONCLUSION: cosinoRmixedeffects package provides the model fitting, estimation and hypothesis testing for the mixed-effects COSINOR model, for the linear and non-linear circadian parameters MESOR, amplitude and acrophase. The model accommodates factors with any number of categories, as well as complex interactions with circadian parameters and categorical factors.
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COVID-19 , RNA Viral , Ritmo Circadiano , Estudos Transversais , Atenção à Saúde , Feminino , Humanos , Masculino , SARS-CoV-2RESUMO
BACKGROUND: Our aim was to investigate if moderate to vigorous physical activity (MVPA), calcium intake interacts with bone mineral density (BMD)-related single nucleotide polymorphisms (SNPs) to influence BMD in 750 Hispanic children (4-19y) of the cross-sectional Viva La Familia Study. METHODS: Physical activity and dietary intake were measured by accelerometers and multiple-pass 24 h dietary recalls, respectively. Total body and lumbar spine BMD were measured by dual energy X-ray absorptiometry. A polygenic risk score (PRS) was computed based on SNPs identified in published literature. Regression analysis was conducted with PRSs, MVPA and calcium intake with total body and lumbar spine BMD. RESULTS: We found evidence of statistically significant interaction effects between the PRS and MVPA on total body BMD and lumbar spine BMD (p < 0.05). Higher PRS was associated with a lower total body BMD (ß = - 0.040 ± 0.009, p = 1.1 × 10- 5) and lumbar spine BMD (ß = - 0.042 ± 0.013, p = 0.0016) in low MVPA group, as compared to high MVPA group (ß = - 0.015 ± 0.006, p = 0.02; ß = 0.008 ± 0.01, p = 0.4, respectively). DISCUSSION: The study indicated that calcium intake does not modify the relationship between genetic variants and BMD, while it implied physical activity interacts with genetic variants to affect BMD in Hispanic children. Due to limited sample size of our study, future research on gene by environment interaction on bone health and functional studies to provide biological insights are needed. CONCLUSIONS: Bone health in Hispanic children with high genetic risk for low BMD is benefitted more by MVPA than children with low genetic risk. Our results may be useful to predict disease risk and tailor dietary and physical activity advice delivery to people, especially children.
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Densidade Óssea , Exercício Físico , Absorciometria de Fóton , Densidade Óssea/genética , Criança , Estudos Transversais , Hispânico ou Latino/genética , HumanosRESUMO
RATIONALE: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health. OBJECTIVE: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility. METHODS: Associations of n-3 PUFA biomarkers (α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (FEV1, FVC, and FEV1/FVC) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N = 16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N = 11,962) and replicated in one cohort (N = 1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of SNP associations and their interactions with n-3 PUFAs. RESULTS: DPA and DHA were positively associated with FEV1 and FVC (P < 0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P2df = 9.4 × 10-9 across discovery and replication cohorts). The rs11693320-A allele (frequency, â¼80%) was associated with lower FVC (PSNP = 2.1 × 10-9; ßSNP = -161.0 ml), and the association was attenuated by higher DHA levels (PSNP×DHA interaction = 2.1 × 10-7; ßSNP×DHA interaction = 36.2 ml). CONCLUSIONS: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.
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Dipeptidil Peptidases e Tripeptidil Peptidases/fisiologia , Ácidos Graxos Ômega-3/sangue , Fenômenos Fisiológicos Respiratórios/genética , Idoso , Biomarcadores/sangue , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Ácidos Docosa-Hexaenoicos/sangue , Ácido Eicosapentaenoico/sangue , Ácidos Graxos Insaturados/sangue , Feminino , Volume Expiratório Forçado/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores Sexuais , Fumar/efeitos adversos , Capacidade Vital/genética , Ácido alfa-Linolênico/sangueRESUMO
PURPOSES: Dietary patterns have been found to be associated with the overall cancer risk and survival. However, the associations of healthy dietary patterns and breast cancer remain unclear. We aimed to conduct a meta-analysis of prospective cohort studies to estimate the pooled results of the association of healthy dietary patterns with breast cancer risk and survival. METHODS: PubMed, EMBASE, and Web of Science were searched for literature published until June 24th, 2018 that examined the associations between healthy dietary patterns and breast cancer risk and survival. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated by using a random-effects model for meta-analysis. RESULTS: There were 32 articles retrieved for the meta-analysis, with 27 for breast cancer risk and five for breast cancer survival. There was a statistically significant lower risk of breast cancer associated with healthy dietary patterns (RR = 0.93, 95% CI: 0.88, 0.98). Subgroup analysis results suggested that there was an inverse association between breast cancer risk and posterori-derived healthy patterns, but no statistically significant associations were found in other stratified subgroups (a priori-derived diet, study region, menopausal status, or breast cancer subtypes). Healthy dietary patterns were associated inversely with all-cause mortality (RR = 0.76, 95% CI: 0.63, 0.92); however, no association was found for breast cancer-specific mortality. CONCLUSIONS: The results suggested that healthy dietary patterns might be associated with a reduced risk of breast cancer and all-cause mortality among breast cancer patients. It could be clinically relevant to promote healthy dietary patterns for breast cancer prevention and improve survival among breast cancer patients.
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Neoplasias da Mama/epidemiologia , Dieta , Neoplasias da Mama/prevenção & controle , Feminino , Humanos , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Late-life depression has become an important public health problem. Available evidence suggests that late-life depression is associated with all-cause and cardiovascular mortality among older adults living in the community, although the associations have not been comprehensively reviewed and quantified.AimTo estimate the pooled association of late-life depression with all-cause and cardiovascular mortality among community-dwelling older adults. METHOD: We conducted a systematic review and meta-analysis of prospective cohort studies that examine the associations of late-life depression with all-cause and cardiovascular mortality in community settings. RESULTS: A total of 61 prospective cohort studies from 53 cohorts with 198 589 participants were included in the systematic review and meta-analysis. A total of 49 cohorts reported all-cause mortality and 15 cohorts reported cardiovascular mortality. Late-life depression was associated with increased risk of all-cause (risk ratio 1.34; 95% CI 1.27, 1.42) and cardiovascular mortality (risk ratio 1.31; 95% CI 1.20, 1.43). There was heterogeneity in results across studies and the magnitude of associations differed by age, gender, study location, follow-up duration and methods used to assess depression. The associations existed in different subgroups by age, gender, regions of studies, follow-up periods and assessment methods of late-life depression. CONCLUSION: Late-life depression is associated with higher risk of both all-cause and cardiovascular mortality among community-dwelling elderly people. Future studies need to test the effectiveness of preventing depression among older adults as a way of reducing mortality in this population. Optimal treatment of late-life depression and its impact on mortality require further investigation.Declaration of interestNone.
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Doenças Cardiovasculares/mortalidade , Depressão/epidemiologia , Vida Independente/estatística & dados numéricos , Mortalidade , Idoso , HumanosRESUMO
Previous studies show inconsistent associations between α-linolenic acid (ALA) and risk of CHD. We aimed to examine an aggregate association between ALA intake and risk of CHD, and assess for any dose-response relationship. We searched the PubMed, EMBASE and Web of Science databases for prospective cohort studies examining associations between ALA intake and CHD, including composite CHD and fatal CHD. Data were pooled using random-effects meta-analysis models, comparing the highest category of ALA intake with the lowest across studies. Subgroup analysis was conducted based on study design, geographic region, age and sex. For dose-response analyses, we used two-stage random-effects dose-response models. In all, fourteen studies of thirteen cohorts were identified and included in the meta-analysis. The pooled results showed that higher ALA intake was associated with modest reduced risk of composite CHD (risk ratios (RR)=0·91; 95 % CI 0·85, 0·97) and fatal CHD (RR=0·85; 95 % CI 0·75, 0·96). The analysis showed a J-shaped relationship between ALA intake and relative risk of composite CHD (χ 2=21·95, P<0·001). Compared with people without ALA intake, only people with ALA intake <1·4 g/d showed reduced risk of composite CHD. ALA intake was linearly associated with fatal CHD - every 1 g/d increase in ALA intake was associated with a 12 % decrease in fatal CHD risk (95 % CI -0·21, -0·04). Though a higher dietary ALA intake was associated with reduced risk of composite and fatal CHD, the excess composite CHD risk at higher ALA intakes warrants further investigation, especially through randomised controlled trials.
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Doença das Coronárias/metabolismo , Doença das Coronárias/prevenção & controle , Dieta , Ácido alfa-Linolênico/efeitos adversos , Adulto , Idoso , Estudos de Coortes , Doença das Coronárias/mortalidade , Relação Dose-Resposta a Droga , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de RiscoRESUMO
The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (P race difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (P race difference=0·56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.
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Envelhecimento , Cardiopatias/genética , Coração/fisiologia , Pneumopatias/genética , Pulmão/fisiologia , Testes de Função Respiratória , Vitamina D/sangue , Adulto , Idoso , População Negra , Estudos Transversais , Feminino , Volume Expiratório Forçado , Genoma Humano , Cardiopatias/prevenção & controle , Humanos , Pneumopatias/prevenção & controle , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Estudos Prospectivos , Análise de Regressão , Fumar , Capacidade Vital , Vitamina D/análogos & derivados , População BrancaRESUMO
Gastrointestinal (GI) B cells and plasma cells (PCs), critical to mucosal homeostasis, play an important role in the host response to HIV-1 infection. Here, high resolution mapping of human B cells and PCs from colon and ileum during both viremic and suppressed HIV-1 infection identified a significant reduction in germinal center (GC) B cells and Follicular Dendritic Cells (FDCs) during HIV-1 viremia. Further, IgA + PCs, the major cellular output of intestinal GCs were significantly reduced during viremic HIV-1 infection. PC-associated transcriptional perturbations, including type I interferon signaling persisted in antiretroviral therapy (ART) treated individuals, suggesting ongoing disruption of the intestinal immune milieu during ART. GI humoral immune perturbations associated with changes in intestinal microbiome composition and systemic inflammation. Herein, we highlight a key immune defect in the GI mucosa due to HIV-1 viremia, with major implications. One Sentence Summary: Major perturbations in intestinal GC dynamics in viremic HIV-1 infection relate to reduced IgA + plasma cells, systemic inflammation and microbiota changes.
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Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colon with sharply rising global prevalence. Dysfunctional epithelial compartment (EC) dynamics are implicated in UC pathogenesis although EC-specific studies are sparse. Applying orthogonal high-dimensional EC profiling to a Primary Cohort (PC; n=222), we detail major epithelial and immune cell perturbations in active UC. Prominently, reduced frequencies of mature BEST4+OTOP2+ absorptive and BEST2+WFDC2+ secretory epithelial enterocytes were associated with the replacement of homeostatic, resident TRDC+KLRD1+HOPX+ γδ+ T cells with RORA+CCL20+S100A4+ TH17 cells and the influx of inflammatory myeloid cells. The EC transcriptome (exemplified by S100A8, HIF1A, TREM1, CXCR1) correlated with clinical, endoscopic, and histological severity of UC in an independent validation cohort (n=649). Furthermore, therapeutic relevance of the observed cellular and transcriptomic changes was investigated in 3 additional published UC cohorts (n=23, 48 and 204 respectively) to reveal that non-response to anti-Tumor Necrosis Factor (anti-TNF) therapy was associated with EC related myeloid cell perturbations. Altogether, these data provide high resolution mapping of the EC to facilitate therapeutic decision-making and personalization of therapy in patients with UC.
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Studies have shown that genetic variations can influence metabolic response to nutrient intake, and that diets rich in fructose contribute to hyperuricemia. In this pilot study, our aim was to determine the variability of serum urate in response to an acute fructose challenge and to investigate if genetic variants would affect this response in young to middle-aged adults who self-reported as Black or White. Fifty-seven participants consumed a fructose-rich beverage after an overnight fast. Blood was drawn at five time points (baseline, 30, 60, 120, and 180 min after consumption). Thirty urate-related single nucleotide polymorphisms (SNPs) were analyzed for their associations with baseline serum urate and its percent changes, using a two-step modeling approach followed by meta-analysis. At baseline, serum urate (mg/dL, mean ± SD) was higher in Whites (5.60 ± 1.01 vs. 5.37 ± 0.96), men (6.17 ± 1.14 vs. 5.24 ± 0.79), and those with obesity (5.69 ± 1.08 vs. 5.42 ± 1.06 vs. 5.34 ± 0.80). Three SNPs were significantly associated with baseline serum urate or its percent changes, and six SNPs were nominally associated with percent changes in serum urate. In summary, our results showed that genetic variants could play a role in short-term urate metabolism.
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Gota , Hiperuricemia , Adulto , Frutose/farmacologia , Humanos , Hiperuricemia/genética , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Fatores de Risco , Ácido ÚricoRESUMO
Background: Chronic obstructive pulmonary disease (COPD) has been considered a risk factor for postoperative respiratory failure after general anesthesia. However, the association between COPD severity and postoperative respiratory failure among COPD patients is unknown. Our aim was to compare the prevalence of postoperative respiratory failure in COPD patients according to disease severity after general anesthesia. Methods: We retrospectively reviewed COPD patients undergoing spinal surgery with general anesthesia at our clinical center between January 2016 and January 2021. These subjects were divided into four groups (group I = mild COPD, group II = moderate COPD, group III = severe COPD, and group IV = very severe COPD) according to their preoperative lung function. The primary endpoint was a respiratory failure 1 week after surgery. The diagnosis of respiratory failure was made with the presence of one or more of the following criteria: prolonged ventilator dependence, unplanned postoperative intubation, and partial pressure of arterial oxygen (PaO2) ≤ 50 mmHg while the patient was breathing ambient air in the hospital. The extubation time, perioperative PaO2 and partial pressure of arterial carbon dioxide (PaCO2), postoperative lung infection, and length of hospitalization were also compared. Results: A total of 120 patients who underwent spinal surgery with general anesthesia were included in this retrospective study. Postoperative respiratory failure occurred in 0 (0.0%) patient in group I, 1 (1.5%) patient in group II, 1 (2.5%) patient in group III, and 1 (14.5%) patient in group IV 1 week after surgery (p = 0.219). The duration of anesthesia was 243.3 ± 104.3 min in group I, 235.5 ± 78.8 min in group II, 196.0 ± 66.3 min in group III, and 173.1 ± 63.7 min in group IV (p < 0.001). Preoperative PaO2, PaCO2, intraoperative oxygenation index [a ratio of PaO2 to fraction of inspired oxygen (FiO2)], and postoperative PaO2 were significantly different among the four groups (p < 0.001, 0.001, 0.046, <0.001, respectively). No significant differences among the four groups were seen in extubation time, pulmonary infection, or hospital stay (p = 0.174, 0.843, 0.253, respectively). The univariate analysis revealed that higher preoperative PaO2 was associated with a lower rate of postoperative respiratory failure (OR 0.83; 95% CI, 0.72 to 0.95; p = 0.007). Conclusion: The severity of COPD as assessed with GOLD classification was not associated with the development of postoperative respiratory failure. However, lower preoperative PaO2 was associated with greater odds of postoperative respiratory failure in COPD patients.
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BACKGROUND: Dietary magnesium deficiency, which is common in modern diet, has been associated with osteoarthritis (OA) susceptibility. Despite this clinical association, no study has addressed if dietary magnesium deficiency accelerates OA development, especially at molecular level. This study aimed to explore aggravating effects of dietary magnesium deficiency on cartilage damage in an injury-induced murine OA model and to determine the underlying mechanism. METHODS: Twelve-week-old C57BL/6J mice subject to injury-induced OA modeling were randomized into different diet groups in which the mice were fed a diet with daily recommended magnesium content (500 mg/kg) or diets with low magnesium content (100 or 300 mg/kg). Articular cartilage damage was evaluated using the OARSI score. To determine molecular mechanisms in vitro, mouse chondrocytes were treated with media of low magnesium conditions at 0.1 and 0.4 mM, compared with normal magnesium condition at 0.7 mM as control. Anabolic and catabolic factors, autophagy markers, ß-catenin, Wnt ligands, and a magnesium channel transient receptor potential cation channel subfamily member 7 (TRPM7) were analyzed by quantitative real-time PCR and immunoblotting. Autolysosomes were detected by DALGreen staining via fluorescence microscopy and autophagosomes were evaluated by transmission electron microscopy. Autophagy markers, ß-catenin, and TRPM7 were assessed in vivo in the mouse cartilage, comparing between dietary magnesium deficiency and normal diet, by immunohistochemistry. RESULTS: Dietary magnesium deficiency aggravated injury-induced cartilage damage, indicated by significant higher OARSI scores. Autophagy markers LC3-II and Beclin-1 were decreased both in low magnesium diet-fed mice and low magnesium-treated chondrocytes. The number of autolysosomes and autophagosomes was also reduced under low magnesium conditions. Moreover, magnesium deficiency induced decreased anabolic and increased catabolic effect of chondrocytes which could be restored by autophagy activator rapamycin. In addition, reduced autophagy under low magnesium conditions is mediated by activated Wnt/ß-catenin signaling. The expression of TRPM7 also decreased in low magnesium diet-fed mice, indicating that downstream changes could be regulated through this channel. CONCLUSIONS: Dietary magnesium deficiency contributes to OA development, which is mediated by reduced autophagy through Wnt/ß-catenin signaling activation. These findings indicated potential benefits of adequate dietary magnesium for OA patients or those individuals at high risk of OA.
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Cartilagem Articular , Deficiência de Magnésio , Osteoartrite , Canais de Cátion TRPM , Animais , Autofagia , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Magnésio/farmacologia , Deficiência de Magnésio/complicações , Deficiência de Magnésio/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Osteoartrite/metabolismo , Canais de Cátion TRPM/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
Understanding the immune response to dengue virus (DENV) is essential for developing a dengue vaccine that is protective against all 4 DENV serotypes. We evaluated the immune response after vaccination (live attenuated tetravalent dengue vaccine TV005 or trivalent admixture) and after challenge with DEN2Δ30 (Tonga/74) to better understand the importance of homotypic immunity in vaccine protection. Significant increases in IP-10 expression were observed following receipt of either the trivalent or tetravalent vaccine. After challenge, a large increase in IP-10 expression was observed in the placebo and trivalent admixture groups but not in the tetravalent vaccine group. MCP-1, IL-1RA, and MIP-1ß exhibited a similar pattern as IP-10. These results demonstrate protective effects of trivalent and tetravalent vaccines against DENV and suggest that the tetravalent vaccine has a better protective effect compared with the trivalent admixture. We also explored the postvaccination and postchallenge immune response differences between Black and White participants. White participants responded to vaccine differently than Black participants; Black participants receiving trivalent and tetravalent vaccines responded strongly and White participants responded only transiently in trivalent group. In response to challenge, White participants elicited a stronger response than Black participants. These results may explain why White participants may have a more vigorous DENV immune response than Black participants, as reported in literature.
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Vacinas contra Dengue , Vírus da Dengue , Dengue , Anticorpos Antivirais , Quimiocina CXCL10 , Humanos , Imunidade Inata , Vacinação/métodos , Vacinas CombinadasRESUMO
BACKGROUND: Glycine is a proteogenic amino acid that is required for numerous metabolic pathways, including purine, creatine, heme, and glutathione biosynthesis. Glycine formation from serine, catalyzed by serine hydroxy methyltransferase, is the major source of this amino acid in humans. Our previous studies in a mouse model have shown a crucial role for the 10-formyltetrahydrofolate dehydrogenase enzyme in serine-to-glycine conversion. OBJECTIVES: We sought to determine the genomic influence on the serine-glycine ratio in 803 Hispanic children from 319 families of the Viva La Familia cohort. METHODS: We performed a genome-wide association analysis for plasma serine, glycine, and the serine-glycine ratio in Sequential Oligogenic Linkage Analysis Routines while accounting for relationships among family members. RESULTS: All 3 parameters were significantly heritable (h2 = 0.22-0.78; P < 0.004). The strongest associations for the serine-glycine ratio were with single nucleotide polymorphisms (SNPs) in aldehyde dehydrogenase 1 family member L1 (ALDH1L1) and glycine decarboxylase (GLDC) and for glycine with GLDC (P < 3.5 × 10-8; effect sizes, 0.03-0.07). No significant associations were found for serine. We also conducted a targeted genetic analysis with ALDH1L1 exonic SNPs and found significant associations between the serine-glycine ratio and rs2886059 (ß = 0.68; SE, 0.25; P = 0.006) and rs3796191 (ß = 0.25; SE, 0.08; P = 0.003) and between glycine and rs3796191 (ß = -0.08; SE, 0.02; P = 0.0004). These exonic SNPs were further associated with metabolic disease risk factors, mainly adiposity measures (P < 0.006). Significant genetic and phenotypic correlations were found for glycine and the serine-glycine ratio with metabolic disease risk factors, including adiposity, insulin sensitivity, and inflammation-related phenotypes [estimate of genetic correlation = -0.37 to 0.35 (P < 0.03); estimate of phenotypic correlation = -0.19 to 0.13 (P < 0.006)]. The significant genetic correlations indicate shared genetic effects among glycine, the serine-glycine ratio, and adiposity and insulin sensitivity phenotypes. CONCLUSIONS: Our study suggests that ALDH1L1 and GLDC SNPs influence the serine-to-glycine ratio and metabolic disease risk.
Assuntos
Glicina Desidrogenase (Descarboxilante) , Resistência à Insulina , Oxirredutases atuantes sobre Doadores de Grupo CH-NH , Serina , Criança , Estudo de Associação Genômica Ampla , Glicina/genética , Glicina Desidrogenase (Descarboxilante)/genética , Glicina Desidrogenase (Descarboxilante)/metabolismo , Hispânico ou Latino/genética , Humanos , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Serina/genéticaRESUMO
OBJECTIVES: We aimed to estimate the association of sleep, sedentary activity and physical activity with cognitive function among older adults, with consideration of the competing nature between variables of activity status. DESIGN: Cross-sectional study. METHODS: A total of 3086 older adults (60 years or older) in the 2011-2014 National Health and Nutrition Examination Survey were included. The Global Physical Activity Questionnaire was used to measure self-reported time for sedentary activity, walking/bicycling and moderate-to-vigorous physical activity (MVPA). Cognitive function was examined using the CERAD Word Learning subtest (memory), Digit Symbol Substitution Test (executive function/processing speed), and Animal Fluency Test (language). Sleep duration was obtained via interview. Isotemporal substitution models using multivariable linear regression were applied to examine the associations of replacing sleep, sedentary activity, walking/bicycling, MVPA with each other and cognitive function, stratified by sleep duration per night (≤7h, >7h). RESULTS: Among participants with sleep duration ≤7h/night, replacing 30min/day of sedentary activity with 30min/day of MVPA or 30min/day was associated with better cognition. Among participants with sleep duration >7h/night, replacing 30min/day of sleep with 30min/day of sedentary activity, walking/bicycling, or MVPA was associated with better cognition. CONCLUSIONS: Replacing sedentary activities with MVPA was associated with favorable cognitive function among older adults sleeping no longer than 7h/night, and replacing excessive sleep with sedentary or physical activities was associated with favorable cognition. Future research is expected to examine the associations of replacing different activity status on long-term cognitive outcomes in longitudinal studies.