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BACKGROUND/AIM: There is lack of studies assessing the correlation between pain scales and acute phase immune response (APR) following surgery. The purpose of this work was to assess the correlation between cysteine protease caspase-1 (Casp1) blood levels and two pain scales in a cohort of 56 midline laparotomy (MLa) patients and to assess their link with other cytokines (CYTs). PATIENTS AND METHODS: Blood levels of Casp1 and other CYTs (IL-18, IL-18BP, IL-1ra, IL-6, IL-8, IL-10, IL-1ß) were measured before operation and following surgery in patients with MLa. Pain levels were assessed using the Numerical Rating Scale (NRS) and Brief Pain Inventory (BPI) scale, both preoperatively and postoperatively. RESULTS: Casp1 blood levels showed an increasing trend at postoperative day 1 (POP1) and this increase was almost significant in a linear mixed effect model (LME) analysis (p=0.06). Additionally, Casp1 blood levels were higher in patients with cancer than those with benign disease and correlated with IL-18 blood levels (r=0.24, p=0.007). Furthermore, Casp1 blood levels correlated with BPIsev (severity) score values in MLa patients (r=-0.49, p=0.048). A significant correlation was also observed between Casp1 blood levels and NRS scores in patients with MLa. CONCLUSION: This is the first report to evaluate two pain surveys (NRS and BPI) in MLa patients in relation to blood levels of Casp1 and eight CYTs. This analysis is important in confirming the significant correlation between NRS and BPI pain scales and Casp1 blood levels. Our study is also the first to demonstrate that adequate postoperative analgesia in patients with MLa provides better functional ability and improved patient satisfaction.
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Caspase 1 , Laparotomia , Neoplasias , Medição da Dor , Dor Pós-Operatória , Humanos , Feminino , Laparotomia/efeitos adversos , Masculino , Caspase 1/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Medição da Dor/métodos , Neoplasias/cirurgia , Neoplasias/sangue , Dor Pós-Operatória/sangue , Dor Pós-Operatória/etiologia , Idoso , Adulto , Citocinas/sangueRESUMO
CONTEXT: The decrease in serum estrogens after menopause is associated with a shift from a gynoid to an android adipose tissue (AT) distribution. Menopausal hormone therapy (HT) mitigates this change and accompanying metabolic dysfunction, but its effects on AT sex steroid metabolism have not been characterized. OBJECTIVE: We studied effects of HT on subcutaneous and visceral AT estrogen and androgen concentrations and metabolism in postmenopausal women. DESIGN, SETTING, PATIENTS, AND INTERVENTIONS: Serum and subcutaneous and visceral AT from 63 postmenopausal women with (n=50) and without (n=13) per oral HT were analyzed for estrone, estradiol, progesterone, testosterone, androstenedione, dehydroepiandrosterone, and serum estrone sulfate using liquid chromatography-tandem mass spectrometry. Steroid sulfatase activity was measured using radiolabeled precursors. mRNA expression of genes encoding sex steroid-metabolizing enzymes and receptors was performed using real-time reverse transcription quantitative polymerase chain reaction. RESULTS: HT users had 4- to 7-fold higher concentrations of estrone and estradiol in subcutaneous and visceral AT, and 30% lower testosterone in visceral AT compared to non-users. Estrogen-to-androgen ratios were 4- to 12-fold higher in AT of users compared to non-users of HT. In visceral AT, estrogen-to-androgen ratios increased with HT estradiol dose. AT to serum ratios of estrone and estradiol remained high in HT users. CONCLUSIONS: Higher local estrogen to androgen ratios and high AT to serum ratios of estrogen concentrations in HT users suggest that HT may significantly influence intracrine sex steroid metabolism in AT, and these local changes could be involved in the preventive effect of HT on menopause-associated abdominal adiposity.
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BACKGROUND/AIM: Cysteine protease caspase-1 (Casp1) plays a crucial role in the conversion of pro-cytokines to active cytokines (CYTs). The purpose of this work was to determine Casp1 blood levels in a cohort of 114 cholecystectomy patients and assess their association with other CYTs and numeric rating scale (NRS) pain scores, postoperatively. PATIENTS AND METHODS: Blood levels of Casp1 and seven CYTs (IL-18, IL-18BP, IL-1ra, IL-6, IL-10, IL-1ß, and IL-8) were measured at three time points; before operation, immediately after operation, and six hours after operation in 114 patients with cholelithiasis (Chole). RESULTS: Casp1 blood levels correlated with NRS pain scores at 24 h following surgery (p=0.016). In addition, Casp1 blood levels correlated significantly to IL-18 blood levels (p<0.001). CONCLUSION: This is the first report to evaluate Casp1 blood levels in Chole patients in correlation with other CYTs. The findings confirm a significant correlation between Casp1 blood levels and NRS pain scores. Moreover, this study provides initial evidence suggesting that inhibition of the activity of Casp1 may reduce postsurgical acute phase immune response possibly through the Casp1/pro-Il-18 pathway.
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Caspase 1 , Colelitíase , Dor Pós-Operatória , Humanos , Feminino , Caspase 1/sangue , Colelitíase/cirurgia , Colelitíase/sangue , Pessoa de Meia-Idade , Masculino , Estudos Prospectivos , Dor Pós-Operatória/sangue , Dor Pós-Operatória/etiologia , Adulto , Idoso , Interleucina-18/sangue , Medição da Dor , Citocinas/sangue , ColecistectomiaRESUMO
Introduction: Systemic and local steroid hormone levels may function as novel prognostic and predictive biomarkers in breast cancer patients. We aimed at developing a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous measurement of multiple, biologically pivotal steroid hormones in human serum and breast cancer tissue. Methods: The quantitative method consisted of liquid-liquid extraction, Sephadex LH-20 chromatography for tissue extracts, and analysis of steroid hormones by liquid-chromatography-tandem mass spectrometry. We analyzed serum and tissue steroid hormone levels in 16 and 40 breast cancer patients, respectively, and assessed their correlations with clinical parameters. Results: The method included quantification of nine steroid hormones in serum [including cortisol, cortisone, corticosterone, estrone (E1), 17ß-estradiol (E2), 17α-hydroxyprogesterone, androstenedione (A4), testosterone and progesterone) and six (including cortisone, corticosterone, E1, E2, A4, and testosterone) in cancer tissue. The lower limits of quantification were between 0.003-10 ng/ml for serum (250 µl) and 0.038-125 pg/mg for tissue (20 mg), respectively. Accuracy was between 98%-126%, intra-assay coefficient of variations (CV) was below 15%, and inter-assay CV were below 11%. The analytical recoveries for tissue were between 76%-110%. Tissue levels of E1 were positively correlated with tissue E2 levels (p<0.001), and with serum levels of E1, E2 and A4 (p<0.01). Tissue E2 levels were positively associated with serum E1 levels (p=0.02), but not with serum E2 levels (p=0.12). The levels of tissue E2 and ratios of E1 to A4 levels (an index for aromatase activity) were significantly higher in patients with larger tumors (p=0.03 and p=0.02, respectively). Conclusions: The method was convenient and suitable for a specific and accurate profiling of clinically important steroid hormones in serum. However, the sensitivity of the profile method in steroid analysis in tissue samples is limited, but it can be used for the analysis of steroids in breast cancer tissues if the size of the sample or its steroid content is sufficient.
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Hydroxysteroid (17beta) dehydrogenase 1 (HSD17B1) is a steroid synthetic enzyme expressed in ovarian granulosa cells and placental syncytiotrophoblasts. Here, HSD17B1 serum concentration was measured with a validated immunoassay during pregnancy at three time points (12-14, 18-20 and 26-28 weeks of gestation). The concentration increased 2.5-fold (P < 0.0001) and 1.7-fold (P = 0.0019) during the follow-up period for control women and women who later developed preeclampsia (PE), respectively, and a significant difference was observed at weeks 26-28 (P = 0.0266). HSD17B1 concentration at all the three time points positively correlated with serum PAPPA measured at the first time point (first time point r = 0.38, P = 1.1 × 10-10; second time point r = 0.27, P = 5.9 × 10-6 and third timepoint r = 0.26, P = 2.3 × 10-5). No correlation was observed between HSD17B1 and placental growth factor (PLGF). Serum HSD17B1 negatively correlated with the mother's weight and body mass index (BMI), mirroring the pattern observed for PAPPA. The univariable logistic regression identified a weak association between HSD17B1 at 26-28 weeks and later development of PE (P = 0.04). The best multivariable model obtained using penalized logistic regression with stable iterative variable selection at 26-28 weeks included HSD17B1, together with PLGF, PAPPA and mother's BMI. While the area under the receiver operating characteristic curve of the model was higher than that of the adjusted PLGF, the difference was not statistically significant. In summary, the serum concentration of HSD17B1 correlated with PAPPA, another protein expressed in syncytiotrophoblasts, and with mother's weight and BMI but could not be considered as an independent marker for PE.
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Biomarcadores , Pré-Eclâmpsia , Proteína Plasmática A Associada à Gravidez , Adulto , Feminino , Humanos , Gravidez , Biomarcadores/sangue , Estradiol Desidrogenases/sangue , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Proteína Plasmática A Associada à Gravidez/metabolismo , Proteína Plasmática A Associada à Gravidez/análiseRESUMO
BACKGROUND/AIM: The acute phase immune response (APR) in midline laparotomy (MLa) patients following surgery has been rarely studied, with no studies assessing the association of blood IL-18 (interleukin-18) and IL-18BP (IL-18 binding protein) values with the numeric rating scale (NRS) pain score following MLa. PATIENTS AND METHODS: Blood levels of seven cytokines (CYT) (IL-18, IL-18BP, IL-1ra, IL-6, IL-8, IL-10, IL-1ß) and high-sensitivity C-reactive protein (hs-CRP) were measured at three time points; before operation (PRE), immediately after operation (POP1), and 24 h after operation (POP2) in 56 patients with MLa. The satisfaction of the patients at 24 h following MLa (SFS24; 0=fully unsatisfied; 10=fully satisfied) was recorded on a 11-point numeric rating scale. RESULTS: In all patients, the IL-18 and IL-18BP blood levels decreased at POP1 and the drop between the preoperative and POP1 levels in the IL-18 and IL-18BP was highly significant (p<0.001). However, the median IL-18 and IL-18BP blood levels increased significantly at POP2 (p<0.001) with the linear mixed-effect model (LME) showing a statistically significant time effect (p<0.001). The hs-CRP blood levels increased significantly at POP2 with the LME model showing a statistically significant time effect. The preoperative and POP2 IL-18 values were clearly higher in patients with cancer versus benign disease (177/182 vs. 135/126, p=0.039/p=0.013, respectively). Interestingly, in all patients of the study, the median IL-18 versus IL-18BP blood levels correlated at POP1 (r=0.315, p=0.036). CONCLUSION: A noteworthy discovery of this study is the correlation of IL-18BP with SFS24 (r=0.361, p=0.05), proposing that APR and quality of life are associated in MLa patients.
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Peptídeos e Proteínas de Sinalização Intercelular , Interleucina-18 , Laparotomia , Neoplasias , Humanos , Interleucina-18/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias/cirurgia , Neoplasias/sangue , Idoso , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Adulto , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análiseRESUMO
BACKGROUND: A substantial proportion of maternal pregnancy complications, adverse birth outcomes and neurodevelopmental delay in children may be attributable to high maternal pre-pregnancy Body Mass Index (BMI). However, BMI alone is insufficient for the identification of all at-risk mothers and children as many women with non-obesity(< 30 kg/m2) or normal weight(18.5-24.99 kg/m2) and their children may suffer from adversities. Evidence suggests that BMI-related metabolic changes during pregnancy may predict adverse mother-child outcomes better than maternal anthropometric BMI. METHODS: In a cohort of 425 mother-child dyads, we identified maternal BMI-defined metabolome based on associations of 95 metabolic measures measured three times during pregnancy with maternal pre-pregnancy BMI. We then examined whether maternal BMI-defined metabolome performed better than anthropometric BMI in predicting gestational diabetes, hypertensive disorders, gestational weight gain (GWG), Caesarian section delivery, child gestational age and weight at birth, preterm birth, admission to neonatal intensive care unit (NICU), and childhood neurodevelopment. Based on metabolic measures with the highest contributions to BMI-defined metabolome, including inflammatory and glycolysis-related measures, fatty acids, fluid balance, ketone bodies, lipids and amino acids, we created a set of maternal high BMI-related polymetabolic risk scores (PMRSs), and in an independent replication cohort of 489 mother-child dyads tested their performance in predicting the same set of mother-child outcomes in comparison to anthropometric BMI. RESULTS: BMI-defined metabolome predicted all of the studied mother-child outcomes and improved their prediction over anthropometric BMI, except for gestational hypertension and GWG. BMI-related PMRSs predicted gestational diabetes, preeclampsia, Caesarian section delivery, admission to NICU, lower gestational age at birth, lower cognitive development score of the child, and improved their prediction over anthropometric BMI. BMI-related PMRSs predicted gestational diabetes, preeclampsia, Caesarean section delivery, NICU admission and child's lower gestational age at birth even at the levels of maternal non-obesity and normal weight. CONCLUSIONS: Maternal BMI-defined metabolome improves the prediction of pregnancy complications, birth outcomes, and neurodevelopment in children over anthropometric BMI. The novel, BMI-related PMRSs generated based on the BMI-defined metabolome have the potential to become biomarkers identifying at-risk mothers and their children for timely targeted interventions even at the level of maternal non-obesity and normal weight.
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Diabetes Gestacional , Hipertensão Induzida pela Gravidez , Obesidade Materna , Pré-Eclâmpsia , Nascimento Prematuro , Pré-Escolar , Recém-Nascido , Gravidez , Feminino , Humanos , Índice de Massa Corporal , Cesárea , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologiaRESUMO
BACKGROUND: Screening for primary aldosteronism is based on measuring aldosterone-to-renin ratio. Non-suppressed renin may cause false negative screening results, and such patients may miss focused, potentially curable treatment. We investigated the association between renal cysts and non-suppressed plasma renin. METHODS: Altogether, 114 consecutive patients with confirmed primary aldosteronism undergoing adrenal vein sampling were prospectively recruited between October 7, 2020 and December 30, 2021. During the procedure, plasma samples for renin analyses were collected from the right and left renal veins and the inferior vena cava. Renal cysts were identified using contrast-enhanced computed tomography. RESULTS: Renal cysts were found in 58.2% of the 114 patients. Neither screening nor renal vein renin concentrations were significantly different in patients with and without cysts, or when the kidneys with and without cysts were evaluated. However, cysts were significantly more prevalent in the "high-normal renin" group (cut point 23.0â mU/L) than in the "low to low-normal renin" group (90.9%, n = 11 vs. 56.0%, n = 102, P = .027, respectively). All patients ≤50 years of age in the "high-normal renin" group had renal cysts. Strong correlations were found between renin concentrations in the right and left renal veins (r = .984), and between renin concentration and renin activity in the inferior vena cava (r = .817). CONCLUSION: Renal cysts are found in the majority of patients with primary aldosteronism, and they may interfere with diagnostics, especially in patients aged 50 years or less. In patients with non-suppressed renin due to renal cysts, aldosterone-to-renin ratio below the diagnostic threshold does not always exclude the diagnosis of primary aldosteronism.
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Cistos , Hiperaldosteronismo , Hipertensão , Doenças Renais Císticas , Humanos , Pessoa de Meia-Idade , Aldosterona/metabolismo , Cistos/complicações , Hipertensão/etiologia , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/complicações , Renina/metabolismo , Estudos Prospectivos , Masculino , Feminino , Adulto , IdosoRESUMO
PURPOSE: To analyze serum estradiol (E2) and estrone (E1) during letrozole treatment and their association to Quality of Life (QoL) and side-effects. METHODS: Postmenopausal breast cancer patients starting adjuvant letrozole were eligible. Serum samples were taken at baseline, three, and 12 months. E2 and FSH were measured with routine chemiluminescent immunoassays. E2 and E1 were analyzed after trial completion with a highly sensitive liquid chromatography-tandem mass spectrometry method (LC-MS/MS) with lower limits of quantification (LLOQ) of 5 pmol/L. QoL was measured at baseline and at 12 months with the EORTC QLQ-C30 and QLQ-BR23 and the Women's Health questionnaires, and menopause-related symptoms with the modified Kupperman Index. RESULTS: Of 100 screened patients 90 completed the trial. Baseline mean LC-MS/MS E2 and E1 were 12 pmol/L (range < 5-57) and 66 pmol/L (< 5-226), respectively. E2 levels measured by immunoassay and LC-MS/MS showed no correlation. E2 and E1 were completely suppressed by letrozole except for one occasion (E1 11 pmol/L at 3 months). Pain, side effects of systemic therapy, vasomotor symptoms, joint and muscle aches, and vaginal dryness increased during letrozole treatment. A high baseline E2 was significantly associated with increased aching joints and muscles, but not with the other side effects. CONCLUSIONS: Letrozole supresses E2 and E1 completely below the LLOQ of the LC-MS/MS in postmenopausal women. High pre-treatment E2 levels were associated with more joint and muscle pain during letrozole. Automated immunoassays are unsuitable for E2 monitoring during letrozole therapy due to poor sensitivity.
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Neoplasias da Mama , Estrona , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Cromatografia Líquida/métodos , Estradiol , Estrogênios/uso terapêutico , Letrozol/uso terapêutico , Pós-Menopausa , Estudos Prospectivos , Qualidade de Vida , Espectrometria de Massas em Tandem/métodosRESUMO
BACKGROUND/AIM: A possible role of interleukin-18 binding protein (IL-18BP) in immune regulation of pain and analgesics following surgery is rarely studied. The aim of this study was to investigate serum IL-18BP values in a cohort of laparoscopic cholecystectomy (LC) and minilaparotomy cholecystectomy (MC) patients and to establish their relationship with other cytokines and number of analgesic doses (NAD) of LC and MC patients postoperatively. PATIENTS AND METHODS: Blood levels of IL-18BP, six other interleukins (IL-18, IL-1ra, IL-6, IL-10, IL-1ß, and IL-8) and high-sensitivity C-reactive protein were measured before operation (PRE), immediately after operation (POP1), and six hours after operation (POP2) in 114 patients with cholelithiasis. RESULTS: Following surgery, the mean serum IL-18BP values correlated significantly to numeric rating scale (NRS) pain scores at 24 hours (r=0.194, p=0.009). In addition, the mean serum IL-18BP values correlated significantly to NAD (r=0.254, p<0.001). CONCLUSION: IL-18BP, a soluble antagonist of IL-18, correlates to NRS and NAD in LC and MC patients, which may support a possible role of IL-18BP in immune regulation of postoperative pain.
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Interleucina-18 , NAD , Humanos , Estudos Prospectivos , Dor Pós-Operatória , AnalgésicosRESUMO
CONTEXT: In non-pregnant population, nonobese individuals with obesity-related metabolome have increased risk for type 2 diabetes and cardiovascular diseases. The risk of these diseases is also increased after gestational diabetes. OBJECTIVE: This work aimed to examine whether nonobese (body mass index [BMI] < 30) and obese (BMI ≥ 30) women with gestational diabetes mellitus (GDM) and obese non-GDM women differ in metabolomic profiles from nonobese non-GDM controls. METHODS: Levels of 66 metabolic measures were assessed in early (median 13, IQR 12.4-13.7 gestation weeks), and across early, mid (20, 19.3-23.0), and late (28, 27.0-35.0) pregnancy blood samples in 755 pregnant women from the PREDO and RADIEL studies. The independent replication cohort comprised 490 pregnant women. RESULTS: Nonobese and obese GDM, and obese non-GDM women differed similarly from the controls across early, mid, and late pregnancy in 13 measures, including very low-density lipoprotein-related measures, and fatty acids. In 6 measures, including fatty acid (FA) ratios, glycolysis-related measures, valine, and 3-hydroxybutyrate, the differences between obese GDM women and controls were more pronounced than the differences between nonobese GDM or obese non-GDM women and controls. In 16 measures, including HDL-related measures, FA ratios, amino acids, and inflammation, differences between obese GDM or obese non-GDM women and controls were more pronounced than the differences between nonobese GDM women and controls. Most differences were evident in early pregnancy, and in the replication cohort were more often in the same direction than would be expected by chance alone. CONCLUSION: Differences between nonobese and obese GDM, or obese non-GDM women and controls in metabolomic profiles may allow detection of high-risk women for timely targeted preventive interventions.
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Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Gravidez , Feminino , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Obesidade , Índice de Massa Corporal , MetabolômicaRESUMO
Pregnane X receptor (PXR) is known to stimulate haem synthesis, but detailed knowledge on the effects of PXR activation on porphyrin metabolism in humans is lacking. We utilized a randomized, crossover, open (blinded laboratory) and placebo-controlled trial with 600-mg rifampicin or placebo dosed for a week to investigate the effects of PXR activation on erythrocyte, plasma, faecal and urine porphyrins. Sixteen healthy volunteers participated on the trial, but the number of volunteers for blood and urine porphyrin analyses was 15 while the number of samples for faecal analyses was 14. Rifampicin increased urine pentaporphyrin concentration 3.7-fold (mean 1.80 ± 0.6 vs. 6.73 ± 4.4 nmol/L, p = 0.003) in comparison with placebo. Urine coproporphyrin I increased 23% (p = 0.036). Faecal protoporphyrin IX decreased (mean 31.6 ± 23.5 vs. 19.2 ± 27.8 nmol/g, p = 0.023). The number of blood erythrocytes was slightly elevated, and plasma bilirubin, catabolic metabolite of haem, was decreased. In conclusion, rifampicin dosing elevated the excretion of certain urinary porphyrin metabolites and decreased faecal protoporphyrin IX excretion. As urine pentaporphyrin and coproporphyrin I are not precursors in haem biosynthesis, increased excretion may serve as a hepatoprotective shunt when haem synthesis or porphyrin levels are increased.
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Porfirinas , Rifampina , Humanos , Eritrócitos , Voluntários Saudáveis , Heme/metabolismo , Porfirinas/metabolismo , Porfirinas/urina , Rifampina/farmacologia , Receptor de Pregnano X/efeitos dos fármacos , Receptor de Pregnano X/metabolismoRESUMO
BACKGROUND/AIM: Anti- and proinflammatory cytokines and plasma high-sensitivity C-reactive protein (hs-CRP) are used to assess inflammatory stress response (ISR) following surgery. However, the serum IL-18 (interleukin-18) cytokine values versus numeric rating scale (NRS) pain score and number of analgesic doses (NAD) postoperatively are unknown. PATIENTS AND METHODS: Blood levels of six interleukins (IL-18, IL-1ra, IL-6, IL-10, IL-1ß, and IL-8) and hs-CRP were measured at three time points; before operation (PRE), immediately after operation (POP1), and six hours after operation (POP2) in 114 patients with cholelithiasis. RESULTS: Following surgery, the blood levels of hs-CRP and IL-1ra, IL-6, IL-10, and IL-1ß cytokines had a trend for increase (p<0.001 and p=0.014, respectively). The serum IL-18 concentrations inversely correlated to NRS and NAD during the first 24 h postoperatively. CONCLUSION: The correlation of IL-18 levels to NRS and NAD values supports the hypothesis that ISR and pain are related.
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Citocinas , Interleucina-18 , Dor Pós-Operatória , Humanos , Analgésicos/uso terapêutico , Proteína C-Reativa/análise , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-10 , Interleucina-6 , Interleucina-8 , Interleucinas , NAD , Dor , Dor Pós-Operatória/diagnósticoRESUMO
Maternal pre-pregnancy obesity and/or higher body mass index (BMI) have been associated with neurodevelopmental and mental health adversities in children. While maternal metabolomic perturbations during pregnancy may underpin these associations, the existing evidence is limited to studying individual metabolites, not capturing metabolic variation specific to maternal BMI, and not accounting for the correlated nature of the metabolomic measures. By using multivariate supervised analytical methods, we first identified maternal early-pregnancy BMI-associated metabolomic component during pregnancy. We then examined whether this component was associated with mental and behavioral disorders in children, improved the prediction of the child outcomes over maternal BMI, and what proportion of the effect of maternal BMI on the child outcomes this component mediated. Early-pregnancy BMI of 425 mothers participating in the PREDO study was extracted from the national Medical Birth Register. During pregnancy, mothers donated up to three blood samples, from which a targeted panel of 68 metabolites were measured. Mental and behavioral disorders in children followed-up from birth until 8.4-12.8 years came from the Care Register for Health Care. Of the 68 metabolites averaged across the three sampling points, 43 associated significantly with maternal early-pregnancy BMI yielding a maternal early-pregnancy BMI-associated metabolomic component (total variance explained, 55.4%; predictive ability, 52.0%). This metabolomic component was significantly associated with higher hazard of any mental and behavioral disorder [HR 1.45, 95%CI(1.15, 1.84)] and relative risk of having a higher number of co-morbid disorders [RR 1.43, 95%CI(1.12, 1.69)] in children. It improved the goodness-of-model-fit over maternal BMI by 37.7-65.6%, and hence the predictive significance of the model, and mediated 60.8-75.8% of the effect of maternal BMI on the child outcomes. Maternal BMI-related metabolomic perturbations during pregnancy are associated with a higher risk of mental and behavioral disorders in children. These findings may allow identifying metabolomic targets for personalized interventions.
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Transtornos Mentais , Mães , Criança , Gravidez , Feminino , Humanos , Índice de Massa Corporal , RiscoRESUMO
Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 × 10-8) with GDM, mapping to/near MTNR1B (P = 4.3 × 10-54), TCF7L2 (P = 4.0 × 10-16), CDKAL1 (P = 1.6 × 10-14), CDKN2A-CDKN2B (P = 4.1 × 10-9) and HKDC1 (P = 2.9 × 10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.
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Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Gestacional/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glucose , Humanos , Polimorfismo de Nucleotídeo Único/genética , GravidezRESUMO
Preterm birth has been linked with postpartum depressive (PPD) disorders and high symptom levels, but evidence remains conflicting and limited in quality. It remains unclear whether PPD symptoms of mothers with preterm babies were already elevated before childbirth, and whether PPD symptoms mediate/aggravate the effect of preterm birth on child mental disorders. We examined whether preterm birth associated with maternal PPD symptoms, depressive symptoms trajectories from antenatal to postpartum stage, and whether PPD symptoms mediated/aggravated associations between preterm birth and child mental disorders. Mothers of preterm (n = 125) and term-born (n = 3033) children of the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study reported depressive symptoms four times within 8 weeks before and twice within 12 months after childbirth. Child mental and behavioral disorder diagnoses until age 8.4-12.8 years came from medical register. Preterm birth associated with higher PPD symptoms (mean difference = 0.19 SD, 95% CI 0.01, 0.37, p = 0.04), and higher odds (odds ratio = 2.23, 95% CI 1.22, 4.09, p = 0.009) of the mother to belong to a group that had consistently high depressive symptoms levels trajectory from antenatal to postpartum stage. PPD symptoms partially mediated and aggravated the association between preterm birth and child mental disorders. Preterm birth, maternal PPD symptoms and child mental disorders are associated, calling for timely prevention interventions.
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Transtornos de Deficit da Atenção e do Comportamento Disruptivo/etiologia , Depressão Pós-Parto/psicologia , Transtornos do Neurodesenvolvimento/etiologia , Adulto , Criança , Pré-Escolar , Parto Obstétrico , Depressão Pós-Parto/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Saúde Mental/tendências , Mães , Parto , Período Pós-Parto , Gravidez , Nascimento Prematuro/psicologia , Fatores de RiscoRESUMO
CONTEXT: Comprehensive assessment of metabolism in maternal obesity and pregnancy disorders can provide information about the shared maternal-fetal milieu and give insight into both maternal long-term health and intergenerational transmission of disease burden. OBJECTIVE: To assess levels, profiles, and change in the levels of metabolic measures during pregnancies complicated by obesity, gestational diabetes (GDM), or hypertensive disorders. DESIGN, SETTING AND PARTICIPANTS: A secondary analysis of 2 study cohorts, PREDO and RADIEL, including 741 pregnant women. MAIN OUTCOME MEASURES: We assessed 225 metabolic measures by nuclear magnetic resonance in blood samples collected at median 13 [interquartile range (IQR) 12.4-13.7], 20 (IQR 19.3-23.0), and 28 (27.0-35.0) weeks of gestation. RESULTS: Across all 3 time points women with obesity [body mass index (BMI)â ≥â 30kg/m2] in comparison to normal weight (BMI 18.5-24.99 kg/m2) had significantly higher levels of most very-low-density lipoprotein-related measures, many fatty and most amino acids, and more adverse metabolic profiles. The change in the levels of most metabolic measures during pregnancy was smaller in obese than in normal weight women. GDM, preeclampsia, and chronic hypertension were associated with metabolic alterations similar to obesity. The associations of obesity held after adjustment for GDM and hypertensive disorders, but many of the associations with GDM and hypertensive disorders were rendered nonsignificant after adjustment for BMI and the other pregnancy disorders. CONCLUSIONS: This study shows that the pregnancy-related metabolic change is smaller in women with obesity, who display metabolic perturbations already in early pregnancy. Metabolic alterations of obesity and pregnancy disorders resembled each other suggesting a shared metabolic origin.
Assuntos
Diabetes Gestacional/sangue , Hipertensão Induzida pela Gravidez/sangue , Metaboloma/fisiologia , Obesidade Materna/sangue , Adulto , Índice de Massa Corporal , Feminino , Idade Gestacional , Humanos , Estudos Longitudinais , Espectroscopia de Ressonância Magnética , Metabolômica/métodos , Obesidade/complicações , Pré-Eclâmpsia , Gravidez , Complicações na Gravidez/sangueRESUMO
OBJECTIVES: Maternal serum inhibin-A, pregnancy associated plasma protein-A (PAPP-A) and PAPP-A2 together with placental growth factor (PlGF), maternal risk factors and uterine artery pulsatility index (UtA PI) were analysed to study their ability to predict pre-eclampsia (PE). STUDY DESIGN: Serial serum samples for the nested case-control study were collected prospectively at 12-14, 18-20 and 26-28 weeks of gestation from 11 women who later developed early-onset PE (EO PE, diagnosis < 34 + 0 weeks of gestation), 34 women who developed late-onset PE (LO PE, diagnosis ≥ 34 + 0 weeks) and 89 controls. MAIN OUTCOME MEASURES: Gestational age -adjusted multiples of the median (MoM) values were calculated for biomarker concentrations. Multivariate regression analyses were performed to combine first trimester biomarkers, previously reported results on PlGF, maternal risk factors and UtA PI. Area under curve (AUC) values and 95% confidence intervals (CIs) for the prediction of PE and its subtypes were calculated. RESULTS: A high first trimester inhibin-A predicted PE (AUC 0.618, 95%CI, 0.513-0.724), whereas PAPP-A and PlGF predicted only EO PE (0.701, 0.562-0.840 and 0.798, 0.686-0.909, respectively). At 26-28 weeks PAPP-A2 and inhibin-A predicted all PE subtypes. In the multivariate setting inhibin-A combined with maternal pre-pregnancy body mass index, prior PE and mean UtA PI predicted PE (0.811,0.726-0.896) and LO PE (0.824, 0.733-0.914). CONCLUSIONS: At first trimester inhibin-A show potential ability to predict not only EO PE but also LO PE whereas PlGF and PAPP-A predict only EO PE. At late second trimester inhibin-A and PAPP-A2 might be useful for short-term prediction of PE.
Assuntos
Inibinas/sangue , Pré-Eclâmpsia/sangue , Proteína Plasmática A Associada à Gravidez/análise , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Pré-Eclâmpsia/diagnóstico , Valor Preditivo dos Testes , Gravidez , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Estudos Prospectivos , Fatores de RiscoRESUMO
PURPOSE: To analyze whether monitoring serum estradiol (E2) levels using a highly sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) method may identify patients with AI failure with E2 levels below the lower limit of quantification (LLOQ) after schwitching from tamoxifen to letrozole. METHODS: In a prospective study of breast cancer patients switching to letrozole treatment after previous tamoxifen, plasma estrogen levels were measured at baseline and after 3- and 12-months using LC-MS/MS. RESULTS: Forty-six patients were classified postmenopausal and entered into the final analysis. Thirty-nine (85%) patients had three- and 12-month E2 concentrations below the LLOQ (5 pmol/L). In the seven patients classified as AI-failures during letrozole treatment, serum E2-MS level rose above 5 pmol/L at 3 months with a mean E2-MS 77.5 pmol/L or 12 months with a mean E2-MS 21 pmol/L. None of the baseline variables i.e., age at diagnosis, age at study entry, age at menarche, BMI, endometrial thickness, total ovarian volume, baseline FSH, E2-IA, or E2-MS were significantly associated with the risk of AI failure in logistic regression. E2 levels at baseline measured by E2-IA did not significantly correlate to the levels measured by E2-MS. CONCLUSIONS: There is a relatively high risk of inadequate estrogen suppression in patients who switch from tamoxifen treatment to AIs. The use of sensitive and specific assays, such as LC-MS/MS methods, to monitor estrogen levels during AI treatment is essential to minimize the risk of a proceeding inefficient endocrine therapy.
Assuntos
Neoplasias da Mama , Tamoxifeno , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Cromatografia Líquida , Estradiol/uso terapêutico , Feminino , Humanos , Letrozol/uso terapêutico , Nitrilas/uso terapêutico , Estudos Prospectivos , Tamoxifeno/uso terapêutico , Espectrometria de Massas em TandemRESUMO
OBJECTIVE: Although the ovaries produce the majority of estrogens in women before menopause, estrogen is also synthesized in peripheral tissues such as adipose tissue (AT). The typical female AT distribution, concentrated in subcutaneous and femoro-gluteal regions, is estrogen-mediated, but the significance of estrogen synthesis in AT of premenopausal women is poorly understood. DESIGN AND METHODS: Serum and subcutaneous and visceral AT homogenates from 28 premenopausal women undergoing non-malignant surgery were analyzed for estrone, estradiol, and serum estrone sulfate (E1S) concentrations with liquid chromatography-tandem mass spectrometry. Isotopic precursors were used to measure enzyme activities of estrone-producing steroid sulfatase and estradiol-producing 17ß-hydroxysteroid dehydrogenases (17ß-HSD). Messenger RNA (mRNA) expression levels of genes for estrogen-metabolizing enzymes were analyzed using real-time reverse transcription quantitative polymerase chain reaction. RESULTS: While estradiol was the predominant circulating active estrogen, estrone dominated in AT, with a higher concentration in visceral than subcutaneous AT (median, 2657 vs 1459 pmol/kg; P = 0.002). Both AT depots converted circulating E1S to estrone, and estrone to estradiol. Median levels of estrone were five to ten times higher in subcutaneous and visceral AT than in serum (P < 0.001) and the estradiol level in visceral AT was 1.3 times higher than in serum (P < 0.005). The local estrone concentration in visceral AT correlated positively with mRNA expression of estrone-producing enzyme aromatase (r = 0.65, P = 0.003). Waist circumference correlated positively with increased estradiol production in subcutaneous AT (r = 0.60, P = 0.039). CONCLUSIONS: Premenopausal AT demonstrated high estrogenic enzyme activity and considerable local estrogen concentrations. This may be a factor promoting female-typical AT distribution in premenopausal women.