Context: Thyroid hormones (THs) have direct and indirect effects on hematopoiesis. However, few studies have directly evaluated the effect of THs on incident anemia among euthyroid subjects. This cohort study aimed to explore whether THs under physiological conditions can affect the development of anemia in the general population. Design: A total of 12,310 participants were enrolled in the cohort study (-5-year follow-up period; mean, 3.1 years). A chemiluminescence immunoassay was used to measure free T3 (FT3), free T4 (FT4), and TSH, and anemia was defined according to the World Health Organization recommendation. THs, TSH, and Hb were assessed yearly during follow-up. Multivariable Cox proportional hazards regression models were used to assess the association between THs, TSH, and incident anemia. Results: The fully adjusted hazards ratios (95% CI) of anemia per 1-unit change in FT3, FT4, and TSH concentrations were 0.70 (0.56, 0.87), 0.93 (0.88, 0.98), and 1.19 (0.94, 1.50) (P < 0.01, P < 0.01, and P = 0.14, respectively). Moreover, a significant and positive association between FT3, FT4, and annual changes in Hb (standard regression coefficients of 0.056 and 0.028, respectively; both P < 0.01) was observed. Similar associations were observed when the participants who had thyroid dysfunction upon follow-up were excluded. Conclusions: The current study demonstrated that THs significantly predict future anemia and annual changes in Hb, even in the euthyroid population.
Context: Late follicular phase elevation in serum progesterone (P) during controlled ovarian hyperstimulation negatively affects the outcome of assisted reproductive technology by contributing to endometrial-embryo asynchrony. There are still no data on lipid metabolite alterations during this process. Objectives: To investigate alterations in the lipid profile during the window of implantation in patients with premature P rise. Design: Lipidomic variations in the endometrium were evaluated by ultrahigh-performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry. Setting: University assisted reproductive medicine unit. Patients or Other Participants: Forty-three patients undergoing in vitro fertilization/intracytoplasmic sperm injection because of a tuba! factor or male factor infertility were included in this study. The patients were divided into a high P group (P >= 1.5 ng/mL, 15 patients) and a normal P group (P < 1.5 ng/mL, 28 patients) on the day of human chorionic gonadotropin administration. Main Outcome Measures: Alterations in lipid metabolites. Results: A total of 1026 ions were identified, and 25 lipids were significantly upregulated. The endometrial lipid profile was characterized by substantial increases in the concentrations of phosphatidylcholine, phosphatidylethanolamine, lysophosphatidylcholine, diacylglycerol, ceramide, phosphatidylinositol, and phosphatidylserine in patients with a premature P rise at the end of the follicular phase. The correlation analysis between P levels and lipids showed a stronger negative correlation between phosphatidylethanolamine or phosphatidylserine and P levels. Conclusions: Premature P elevation disrupts the lipid homeostasis of the endometrium during the peri-implantation period. The altered lipid levels may impair endometrial receptivity and early embryo implantation.
Objectives: This study aimed to investigate the associations between trimethylamine N-oxide (TMAO) and related metabolites in early pregnancy and the risk of gestational diabetes mellitus (GDM). Design: A prospective cohort of 22,302 pregnant women from 2010 to 2012 in Tianjin, China, was used to perform a nested case-control study. A total of 243 women with GDM and 243 women without GDM matched by maternal age (+/- 1 year) were used as cases and controls, respectively. Conditional logistic regression and restricted cubic spline were used to examine the full-range risk associations between individual TMAOs metabolites at the first antenatal care visit with GDM. Trimethylamine conversion ratio (TMA(R)) was defined as trimethylamine (TMA)/its precursors, and trimethylamine N-oxide conversion ratio (TMAO(R)) was defined as TMAO/TMA. An additive interaction between high TMA(R) and low TMAO(R) indicates a state of TMA accumulation, and a mathematical interaction between high TMA(R) and high TMAO R indicates accumulation of TMAO. Results: TMA was linearly associated with GDM, whereas TMA precursors and TMAO were inversely associated with GDM with clear threshold effects, i.e., 16 nmol/mL for TMAO, 200 nmol/mL for betaine, 112 nmol/mL for L-carnitine, and 110 and 270 nmol/mL for cholinechloride (a U-shaped relationship). Copresence of TMA(R) >0.35 and TMAO(R) <0.15 was associated with a markedly higher OR (11.16; 95% CI, 5.45 to 22.8), compared with TMA(R) >0.35 only (OR = 1.71; 95% CI, 0.42 to 6.95) or TMAO(R) <= 0.15 only (OR = 2.06; 95% CI, 1.09 to 3.90), with a significant additive interaction. However, the mathematical interaction was nonsignificant. Conclusions: TMAO metabolites in the early pregnancy were associated with the risk of GDM, whereas TMA was more likely to play a causal role in GDM.
Context: Maternal thyroid hormones during pregnancy play a critical role in fetal development. However, whether maternal heavy metal exposure affects their thyroid hormones and the effects on fetal growth are still unclear. Objective: To explore the effect of heavy metal exposure on maternal thyroid hormones and the potential mediation role of thyroid hormones on birth outcomes. Methods: Concentrations of heavy metals in urine samples and thyroid hormones in blood samples of 675 pregnant women were measured during early pregnancy in a cohort study conducted in China. Multivariable linear regressions were applied to explore the associations of maternal urinary heavy metal levels with both maternal thyroid hormones and birth outcomes. Mediation analyses were performed to assess the mediation role of thyroid hormones in these associations. Results: Maternal urinary vanadium (V) exhibited an inverse association with free T3 (FT3) and FT3/free T4 (FT4) ratio levels. Urinary arsenic (As) and lead (Pb) had inverse relationships with FT3. We also observed the positive associations of maternal FT3 and FT3/FT4 ratio with birthweight. The mediation analyses suggested that 5.33% to 30.57% of the associations among V, As, and Pb levels and birth size might be mediated by maternal FT3 or FT3/FT4 ratio. Conclusions: We have shown that maternal exposures to V, As, and Pb at early pregnancy were associated with decreased maternal FT3 or FT3/FT4 ratio, which might contribute to reduced birthweight. Mediation analyses indicated that maternal thyroid hormone was a possible mediator of the association between urinary heavy metals and birth size.
Purpose: The mortality risk of stage II differentiated thyroid cancer (DTC) based on the American Joint Committee on Cancer (AJCC) staging system requires further investigation. Methods: Retrospective study of DTC in the US Surveillance, Epidemiology, and End Results program for disease-specific mortality risk in various AJCC stages, with patient age stratification of stage II disease. Results: Using AJCC staging system 6.0, hazard ratios (HRs) of mortality for stage II DTC in patients <45 yo and patients >= 45yo and stages III, IVA, IVB, and IVC compared with stage I were 46.95, 4.95, 9.82, 57.37, 222.10, and 468.68, respectively, showing a robustly higher mortality risk in stage II disease in patients <45 yo than in older patients (P < 0.001), comparable with stage IVA (P = 0.482). Similar results were obtained with AJCC 7.0. With AJCC 8.0, HRs of mortality for stage II in patients <55 yo and patients >= 55 yo and stages III, IVA, and IVB compared with stage I were 75.16, 11.23, 69.45, 134.94, and 235.70, respectively, showing a robustly higher risk in stage II disease in patients <55 yo than in older patients (P < 0.001), comparable with stage III (P = 0.57). Kaplan-Meier survival curves displayed a sharp decline with stage II disease in patients <45/55 yo compared with older patients. Conclusions: The mortality risk of stage II DTC was sharply differentiated at patient age 45/55 years, being robustly high in younger patients and comparable with stage III/IVA. This emphasizes the importance of considering age when managing stage II DTC and not treating it as a uniformly low-risk disease.
Context: Type 2 diabetes (T2D) and pancreatogenic diabetes are both associated with loss of functional beta-cell mass. Previous studies have proposed b-cell dedifferentiation as a mechanism of islet beta-cell failure, but its significance in humans is still controversial. Objective: To determine whether beta-cell dedifferentiation occurs in human T2D with adequate glucose control and in nondiabetic chronic pancreatitis (NDCP), we examined pancreatic islets from nine nondiabetic controls, 10 patients with diabetes with well-controlled fasting glycemia, and four individuals with NDCP. Design: We calculated the percentage of hormone-negative endocrine cells and multihormone endocrine cells and scored the pathological characteristics; that is, inflammatory cell infiltration, fibrosis, atrophy, and steatosis, in each case. Results: We found a nearly threefold increase in dedifferentiated cells in T2D with adequate glucose control compared with nondiabetic controls (10.0% vs 3.6%, T2D vs nondiabetic controls, P < 0.0001). The dedifferentiation rate was positively correlated with the duration of diabetes. Moreover, we detected a considerable proportion of dedifferentiated cells in NDCP (10.4%), which correlated well with the grade of inflammatory cell infiltration, fibrosis, and atrophy. Conclusions: The data support the view that pancreatic beta-cells are dedifferentiated in patients with T2D with adequate glucose control. Furthermore, the existence of abundant dedifferentiated cells in NDCP suggests that inflammation-induced beta-cell dedifferentiation can be a cause of pancreatogenic diabetes during disease progress.
Purpose: To investigate the importance of dietary selenium (Se) for hyperthyroidism. Methods: We performed a more in-depth analysis of a large cross-sectional study of 6152 participants from two counties within the Shaanxi Province, China. These counties are characterized by different habitual Se intake. We investigated the effects of a different dietary Se supply (0.02, 0.18, 0.6, or 2.0 ppm Se) on disease development in a mouse model of Graves disease (GD). Results: The cross-sectional study revealed a comparable prevalence of hyperthyroidism, irrespective of Se intake, in both counties. However, an unexpected sex-specific difference was noted, and Se deficiency might constitute a risk factor for hyperthyroidism, especially in males. In a mouse model, pathological thyroid morphology was affected, and greater Se intake exerted some protecting effects on the pathological distortion. Circulating thyroid hormone levels, malondialdehyde concentrations, total antioxidant capacity, and the titer of GD-causing TSH receptor autoantibodies were not affected by Se. Expression analysis of the transcripts in the spleen indicated regulatory effects on genes implicated in the immune response, erythropoiesis, and oxygen status. However, the humoral immune response, including the CD4/CD8 or T-helper 1/T-helper 2 cell ratio and the concentration of regulatory T cells, was similar between the experimental groups, despite the difference in Se intake. Conclusions: Our data have highlighted a sexual dimorphism for the interaction of Se and thyroid disease risk in humans, with indications of a local protective effects of Se on thyroid gland integrity, which appears not to be reflected in the circulating biomarkers tested.
Context: Endothelium guarantees vascular homeostasis by the opposite action of substances by vasodilating/antithrombogenic and vasoconstricting/prothrombotic activities. Obesity is characterized by endothelial dysfunction associated with a condition of vascular low-grade inflammation. Evidence Acquisition: Analysis of available basic or clinical papers published in peer-reviewed international journals on microcirculation and obesity. Evidence Synthesis: Vascular low-grade inflammation, which characterizes obesity, is secondary to abnormal production of proinflammatory cytokines, including TNF-alpha. TNF-alpha, generated either in small vessels or within the perivascular adipose tissue (PVAT) of patients with obesity, stimulates reactive oxygen species generation, mainly through NAD(P)H oxidase activation, which in turn reduces nitric oxide (NO) availability. These aspects are highlighted by the insulin resistance status and macronutrient intake that characterize the obesity condition. Oxidant excess has also been proposed as a mechanism whereby TNF-alpha interferes with the endothelin-1/NO system at the level of small vessels from patients with obesity. Conclusions: In obesity, microvasculature from visceral fat is an important source of low-grade inflammation and oxidative stress that, together with the PVAT, directly contribute to vascular changes, favoring the development and acceleration of the vascular atherothrombotic process in this clinical condition.
Context: N-6-methyladenosine (m(6)A) in mRNA is the most abundant and reversible modification. However, the mechanism behind the decrease in m(6)A in patients with type 2 diabetes (T2D) has not yet been thoroughly investigated. Objective: To clarify whether glucose is involved in the dynamic regulation of m(6)A in T2D and to identify a possible underlying mechanism. Methods: Liquid chromatography/electrospray ionization/tandem mass spectrometry and quantitative PCR were performed to determine the m(6)A content and the mRNA expression of target genes in 102 patients with T2D and 107 controls. An additional 12 patients with normal fasting blood glucose, emergency hyperglycemia, or emergency hypoglycemia, as well as HepG2 cells with high-glucose treatment and FTO knockout or overexpression were used to confirm the initial observations in patients. Results: In patients with T2D, the m(6)A content was decreased, and mRNA expression levels of FTO, METTL3, METTL14, and WTAP were increased. Interestingly, the m(6)A content was negatively associated with mRNA expression levels of METTL3, METTL14, and FTO. Moreover, FTO was positively correlated with serum glucose. In HepG2 cells, high glucose upregulated FTO protein, whereas it had no significant effect on METTL3 or METTL14. Additionally, mRNA expression levels of FOXO1, G6PC, and DGAT2 were significantly increased and positively correlated with FTO and serum glucose in patients. Conclusions: Our data revealed that in patients with T2D, high-glucose-enhanced FTO mRNA expression resulted in a decrease in m(6)A. The lower m(6)A content might be responsible for the upregulation of methyltransferases. Additionally, FTO induced mRNA expression of FOXO1, G6PC, and DGAT2 and was closely associated with glucose metabolism.
Context: Maternal obesity increases the risk of preterm delivery. Obesity is known to be associated with altered lipid metabolism. Objective: To investigate the associations between high maternal triglyceride (mTG) levels during early pregnancy and risks of preterm delivery stratified by early pregnancy body mass index (BMI). Design: Retrospective cohort study. Setting: University-based maternity center. Patients: 49,612 women with singleton pregnancy who underwent fasting serum lipid screening during early pregnancy. Main Outcome Measures: Risk of preterm delivery (total, <37 weeks; early, 28 to 33 weeks; and late, 34 to 36 weeks). Results: Among women enrolled, 2494 had a preterm delivery, including 438 early preterm and 2056 late preterm delivery. High mTG (>90th percentile, 2.04 mM) was associated with shortened gestation. Risks of total, early, and late preterm deliveries increased with mTG levels, and the high mTG-related risk was highest for early preterm delivery [adjusted odds ratio (AOR) 1.72; 95% CI, 1.30 to 2.29]. After stratification by BMI, high mTG was associated with risk of preterm delivery in both overweight or obese (OWO) women (AOR 1.32; 95% CI, 1.02 to 1.70) and women with normal BMI (AOR 1.36; 95% CI, 1.16 to 1.59). In additional sensitivity analyses, we found that high mTG was related to higher risks of preterm delivery among OWO women and women with normal BMI (AOR, 1.54; 95% CI, 1.07 to 2.22 and 1.62, 1.34 to 1.96, respectively), especially early preterm delivery (AOR 2.47; 95% CI, 1.19 to 5.10, and AOR 2.50; 95% CI, 1.65 to 3.78, respectively). Conclusions: High mTG level during early pregnancy increased the risks of preterm delivery not only in OWO women but also in women with normal BMI.
Context: Elevated blood triglyceride levels are known to increase the risks of diabetes and prediabetes. However, it is still unclear whether elevated triglyceride levels are associated with inadequate glycemic control in patients with type 2 diabetes mellitus. Objective: To investigate the association between elevated triglyceride levels and inadequate glycemic control among insulin-treated patients with type 2 diabetes mellitus. Design, Setting, and Patients: We recruited 20,108 patients with type 2 diabetes mellitus who were treated with a sufficient dose of insulin. These patients were from the 2013 China National HbA(1c) Surveillance System study conducted in Mainland China. Multivariate logistic regressions were used to assess the association of triglyceride level with inadequate glycemic control. Results: Overall, 56.0% of the subjects had elevated triglyceride levels (>= 1.70 mmol/L); prevalence of HbA(1c) >= 7.0% (53 mmol/mol) and >= 6.5% (48 mmol/mol) was 67.2% and 83.4%, respectively. The adjusted ORs (95% CIs) of HbA(1c) >= 7.0% were 1.06 (0.98, 1.15), 1.35 (1.23, 1.48), and 3.12 (2.76, 3.53) for those with triglyceride levels in ranges of 1.70 to 2.29, 2.30 to 3.39, and >= 3.40 mmol/L, respectively, compared with those with triglyceride levels of <1.70 mmol/L. There was a similar association between triglyceride levels and HbA(1c) >= 6.5%. This association was confirmed by subgroup analyses. There was also a strong nonlinear dose-response relationship between triglyceride level and inadequate glycemic control. Conclusions: Elevated triglyceride levels were strongly associated with inadequate glycemic control; thus, suppressing triglyceride levels may attain more optimal glycemic control in patients with type 2 diabetes mellitus.
Context: Adrenal venous sampling (AVS), with or without adrenocorticotropic hormone (ACTH) stimulation, is the test of choice to identify patients with a surgically curable subtype of primary aldosteronism (PA). Whether AVS with ACTH stimulation is more effective than AVS without ACTH stimulation remains controversial. Objective: To compare the effectiveness of AVS with ACTH stimulation and AVS without ACTH stimulation in patients with PA. Design: The Cochrane Library, PubMed, Embase, and Web of Science databases were searched to identify relevant articles. All cohort studies comparing the two techniques (AVS with ACTH stimulation and AVS without ACTH stimulation in a patient with PA) were included in the analysis. Results: A total of 14 studies met the inclusion criteria, and they were analyzed. AVS with ACTH stimulation did not significantly reduce the number of incorrect lateralization more than AVS without ACTH stimulation in patients with PA (OR: 0.76; 95% CI: 0.36, 1.59; P = 0.47). AVS with ACTH stimulation significantly reduced the number of unsuccessful cannulations of both adrenal veins more than AVS without ACTH stimulation in patients with PA (OR: 0.26; 95% CI: 0.17, 0.40; P < 0.00001). For subgroup analyses, it also significantly reduced the number of unsuccessful cannulations of left adrenal vein and right adrenal vein (OR: 0.14, 95% CI: 0.06, 0.33, P < 0.00001; and OR: 0.30, 95% CI: 0.12, 0.71, P = 0.007, respectively). Conclusion: AVS with ACTH stimulation can significantly reduce the number of unsuccessful cannulations, without significantly reducing the number of incorrect lateralization. Further studies are still needed to verify these findings.
Context: The high mobility group AT hook 2 (HMGA2) gene was previously identified in a genome-wide association study as a candidate risk gene that might be related to polycystic ovary syndrome (PCOS). Whether HMGA2 contributes to promoting granulosa cell (GC) proliferation in PCOS remains unknown. Objective: We sought to determine whether HMGA2 is involved in the ovarian dysfunction of PCOS and in the mechanism of increased GC proliferation. Patients and Cells: mRNA expression was analyzed in ovarian GCs from 96 women with PCOS and 58 healthy controls. Immortalized human GCs (KGN and SVOG cells) were used for the mechanism study. Main Outcome Measures: mRNA expression in ovarian GCs was measured using quantitative RT-PCR, and KGN cells were cultured for proliferation assays after overexpression or knockdown of target genes. Protein expression analysis, luciferase assays, and RNA binding protein immunoprecipitation assays were used to confirm the mechanism study. Results: HMGA2 and IGF2 mRNA binding protein 2 (IMP2) were highly expressed in the GCs of women with PCOS, and the HMGA2/IMP2 pathway promoted GC proliferation. Cyclin D2 and SERPINE1 mRNA binding protein 1 were regulated by IMP2 and were highly expressed in women with PCOS. Conclusions: The HMGA2/IMP2 pathway was activated in women with PCOS and promoted the proliferation of GCs. This might provide new insights into the dysfunction of GCs in PCOS.
Context: It is uncertain which osteoporosis therapy is more effective: bisphosphonates or denosumab. Objective: To determine whether denosumab therapy increases bone mineral density (BMD) and reduces fracture risk more so than bisphosphonates in patients with low BMD or osteoporosis. Methods: The PubMed, Embase, and the Cochrane Library databases were searched through November 2018 for head-to-head, randomized, controlled trials comparing denosumab and bisphosphonates among adult patients with low BMD or osteoporosis. Random-effects models were used. Results: We identified 10 eligible trials including 5361 participants. Denosumab increased BMD more than bisphosphonate at 12 months (mean difference, 1.42%; 95% CI, 0.95% to 1.89%; P < 0.001) at lumbar spine, 1.11% (95% CI, 0.91% to 1.30%; P < 0.001) at total hip, and 1.00% (95% CI, 0.78% to 1.22%; P < 0.001) at femoral neck. At 24 months, the respective increase differences were 1.74% (95% CI, 1.05% to 2.43%; P < 0.001), 1.22% (95% CI, 0.66% to 1.77%; P < 0.001), and 1.19% (95% CI, 0.65% to 1.72%; P < 0.001). There was no difference in fracture end point at 12 months, but denosumab had a lower osteoporotic fracture incidence than alendronate at 24 months (risk ratio, 0.51; 95% CI, 0.27 to 0.97). Conclusion: Denosumab improved BMD significantly more than bisphosphonate treatment at the lumbar spine, total hip, and femoral neck at 12 and 24 months. Only one study demonstrated greater osteoporotic fracture reduction with denosumab treatment. Longitudinal studies with longer follow-up and large sample size are needed to confirm the efficacy difference.
Context: Unique features of local immunity in thyroid-associated ophthalmopathy (TAO) may affect disease progression. Objective: To investigate the association between the orbital immune microenvironment and TAO development. Design/Setting/Participants: TAO and control orbital connective tissues were collected. Main Outcome Measures: Single-cell sequencing examined orbital lymphocytic infiltrates. Multicolor flow cytometry explored the phenotypes of different cell subsets and in vitro models for cell functional studies. Coculture experiment and western blotting assay were used to determine underlying mechanism of the enhanced T helper 17 (Th17) cell pathway. Results: The TAO orbital microenvironment was composed of natural killer cells, dendritic cells, macrophages, T cells, plasma cells, and CD34(+) orbital fibroblasts, but few B cells. Increases in CD3(+)CD8(-) IL-17A-producing and RAR-related orphan receptor (ROR)gamma t-expressing T cells and in CD3(+)CD8(-) IL-13-producing and GATA3-expressing T cells suggested Th17 and Th2 cell responses in TAO orbits. Increased interferon-gamma (IFN-gamma)-producing and ROR gamma t(+)Tbet(+) T cells indicated a Th1-like phenotype of orbital-infiltrating Th17 cells. Higher IL-23R and IL-1R expression and lower IL-21R expression were also observed on Th17 cells in TAO orbits. Multivariate analyses revealed that the Th17 pathway [IL-17A (P = 0.001), IFN-gamma (P = 0.009), ROR gamma t (P = 0.003), IL-23R (P = 0.033), IL-21R (P = 0.019)], and Th2 pathway [IL-13 (P = 0.015), GATA3 (P = 0.012)] were associated with TAO. IL-17A, IL23R, and IL-1R correlated with clinical activity score and visual acuity. CD34(+) orbital fibroblasts exhibited distinct cell surface marker expression and promoted IL-23R and IL-1R expression on T cells to facilitate the Th17-cell phenotype through prostaglandin E-2-EP2/EP4-cAMP signaling. Conclusion: Our study addresses the importance of retroorbital immunity and suggests possible means of disrupting TAO pathogenesis.