Background: The association between high thyrotropin receptor antibody (TRAb) titers at diagnosis and long-term outcomes following prolonged antithyroid drug (ATD) therapy in Graves’ disease (GD) remains unclear. This study examined TRAb dynamics and outcomes in high-titer patients receiving prolonged ATD. Methods: In this retrospective cohort (2018–2021), 1,148 of 3,052 newly diagnosed GD patients met inclusion criteria (≥18-month ATD course, TRAb negativity before withdrawal, and ≥12-month follow-up). Initial TRAb levels were defined as low-titer (<5.25 IU/L, 3×upper normal limit [UNL]), intermediate-titer (5.25–10.5 IU/L), and high-titer (>10.5 IU/L, 6×UNL). Outcomes included TRAb dynamics, treatment duration, and relapse. Results: High-titer patients required longer therapy (50 months vs. 30 months vs. 22 months, P<0.001) and slower thyroid-stimulating hormone normalization (6 months vs. 4 months vs. 2 months, both P<0.001). TRAb negativity at 24/48 months occurred in 91.85%/99.26% (low-titer), 52.38%/75.24% (intermediate-titer), and 12.70%/52.68% (high-titer) (P<0.001). High-titer patients showed fluctuant (46.20%) or smoldering (28.89%) trends. Remission rates declined with higher TRAb titer (60.45% vs. 42.70% vs. 30.47%, P<0.001). High-titer patients showed increased risk of persistent TRAb positivity (2.17-fold; 95% confidence interval [CI], 1.55 to 3.05) and relapse (1.66-fold; 95% CI, 1.45 to 3.22). Thresholds of 10.90 IU/L and 16.01 IU/L predicted positivity and relapse, respectively. Definitive therapy post-relapse was more common in high-titer patients (38.29% vs. 16.98% in low-titer, P<0.001). Conclusion High TRAb titers strongly predict persistent TRAb positivity and relapse after ATD withdrawal. Cut-off at 10.90 and 16.01 IU/L may guide prognosis and treatment.

Echinomycin is a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity, which plays a crucial role in ovarian ovulation in mammalians. The present study was designed to test the hypothesis that hypoxia-inducible factor (HIF)-1alpha-mediated endothelin (ET)-2 expressions contributed to ovarian ovulation in response to human chorionic gonadotropin (hCG) during gonadotropin-induced superuvulation. By real-time RT-PCR analysis, ET-2 mRNA level was found to significantly decrease in the ovaries after echinomycin treatment, while HIF-1alpha mRNA and protein expression was not obviously changed. Further analysis also showed that these changes of ET-2 mRNA were consistent with HIF-1 activity in the ovaires, which is similar with HIF-1alpha and ET-2 expression in the granulosa cells with gonadotropin and echinomycin treatments. The results of HIF-1alpha and ET-2 expression in the granulosa cells transfected with cis-element oligodeoxynucleotide (dsODN) under gonadotropin treatment further indicated HIF-1alpha directly mediated the transcriptional activation of ET-2 during gonadotropin-induced superuvulation. Taken together, these results demonstrated that HIF-1alpha-mediated ET-2 transcriptional activation is one of the important mechanisms regulating gonadotropin-induced mammalian ovulatory precess in vivo.
Animals ; Cells, Cultured ; Chorionic Gonadotropin/*pharmacology ; Echinomycin/*pharmacology ; Endothelin-2/genetics/*metabolism ; Female ; Gonadotropins, Equine/*pharmacology ; Granulosa Cells/drug effects/metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors/genetics/metabolism/physiology ; Oligonucleotides/genetics ; Ovary/cytology/drug effects/physiology ; Rats ; Rats, Sprague-Dawley ; Superovulation/*drug effects ; Transcriptional Activation

Objective To investigate the effect of matrix metalloproteinas-9 (MMP-9) and high sensitive C-reactive protein (hs-CRP) in type 2 diabetes mellitus (T2DM) combined with coronary heart disease(CHD). Methods Thirty-one patients with T2DM combined with CHD(T2DM combined with CHD group) ,50 patients with CHD (CHD group) and 30 healthy volunteers (control group) were studied. Serum MMP-9 was measured by ELISA, and serum hs-CRP was measured by scattering immunoturbidimetric assay. Results The level of MMP-9 in T2DM combined with CHD group (409.62 μg/L) was significantly higher than that in CHD group (263.40 μg/L) and control group [(196.15 ±44.89) μg/L] (P < 0.05).The level of hs-CRP in T2DM combined with CHD group (17.20 mg/L) was significantly higher than that in CHD group (4.57 mg/L) and control group [(1.52±0.78) mg/L] (P <0.01). MMP-9 wa significantly related with hs-CRP in T2DM combined with C HD group (r = 0.482,P < 0.01). Conclusion The serum M MP-9 and hs-CRP levels are closely associated with the occurrence and development of diabetes related coronary atherosclerosis.