[Association of maternal isolated thyroid peroxidase antibody positive in the first trimester with fetal growth].

OBJECTIVE: To investigate the association of isolated thyroid peroxidase antibody (TPOAb) positive in the first trimester with fetal growth. METHODS: A total of 16 446 pregnant women were included in the birth cohort study, whose last menstrual period was between May 2016 and April 2019 and with singleton pregnancy. Maternal serum samples were collected when they firstly came for prenatal care in the first trimester. The pregnant women were consecutively seen and followed in the hospital and the information of pregnant women was extracted from the electronic medical information system. The pregnant women were divided into isolated TPOAb positive group (n=1 654) and euthyroid group (n=14 792). Three fetal ultrasound examinations were scheduled during the routine prenatal visits at the hospital and were performed by trained sonographers. All fetal growth indicators were quantified as gestational age- and gender- adjusted standard deviation score (Z-score) using the generalized additive models for location, scale and shape (GAMLSS). Fetal growth indicators included estimated fetal weight (EFW), abdominal circumference (AC), biparietal diameter (BPD), femur length (FL) and head circumference (HC). Fetal growth restriction (FGR) was defined as AC or EFW Z-score＜3rd centile based on clinical consensus. Generalized estimating equation (GEE) analysis was applied to assess the association of maternal isolated TPOAb positive with fetal growth. The generalized linear model was further used to analyze the association between isolated TPOAb positive and fetal growth indicator at different gestational ages when the fetal growth indicator was significantly associated with isolated TPOAb positive in the GEE mo-del. RESULTS: The median gestational age at three ultrasound measurements was 23.6 (23.3, 24.1), 30.3 (29.7, 30.9), 37.3 (37.0, 37.7) weeks, respectively. The BPD Z-score was higher in isolated TPOAb positive women, compared with the euthyroid pregnant women after adjustment (ß=0.057, 95%CI: 0.014-0.100, P=0.009). The generalized linear model showed the BPD Z-score was higher in the isolated TPOAb positive women at the end of 21-25 weeks (ß=0.052, 95%CI: 0.001-0.103, P=0.044), 29-32 weeks (ß=0.055, 95%CI: 0.004-0.107, P=0.035) and 36-40 weeks (ß=0.068, 95%CI: 0.011-0.125, P=0.020), compared with the euthyroid pregnant women. There was no difference in other fetal growth indicators (EFW, AC, FL and HC) and FGR between the isolated TPOAb positive and euthyroid pregnant women. CONCLUSION: The BPD Z-score was slightly increased in the isolated TPOAb positive pregnant women in the first trimester, while other fetal growth indicators were not changed. The reproducibility and practical significance of this result need to be confirmed.

Expression profiling of Ca(2+)/calmodulin-dependent signaling molecules in the rat dorsal and ventral hippocampus after acute lead exposure.

The septal and temporal poles of the hippocampus differ markedly in their anatomical organization, but whether these distinct regions exhibit differential neurochemical profiles underlying lead (Pb(2+)) neurotoxicity remains to be determined. In the present study, we examined changes in the expression of Ca(2+)/calmodulin-dependent enzymes, including calpain, calcineurin, phospho-CaMKII (Thr286) and neuronal nitric oxide synthase (nNOS), in the rat dorsal and ventral hippocampus (DH and VH) after acute Pb(2+) exposure. Five days after Pb(2+) exposure, we observed constitutively active forms of calcineurin (45 kDa and 48 kDa) in ventral portions of the hippocampus, a result consistent with the observed calpain activation that is indicated by the breakdown of spectrin in this region. Our data demonstrate that nNOS expression is significantly higher in the ventral region of the hippocampus when compared to the dorsal region, whereas phosphorylation of CaMKII (Thr286) is less pronounced in the ventral portion of the hippocampus and more pronounced in dorsal regions after acute Pb(2+) exposure. Thus, it appears likely that the ventral region of hippocampus is more vulnerable to the neurotoxic effects of Pb(2+) than the dorsal region. Taken together, the present data suggest that acute lead exposure leads to differential expression patterns of Ca(2+)/calmodulin-dependent enzymes along the dorsoventral axis of the hippocampus.

Targeting nitrosative stress for neurovascular protection: new implications in brain diseases.

Nitric oxide/peroxynitrite signaling is associated with manifold neurovascular pathogenic cascades that lead to neurodegenerative diseases, including ischemic stroke, Alzheimer's disease, and vascular dementia. Considerable evidence suggests that reactive nitrogen species as mediators of nitrosative stress could damage biomolecules and subsequently facilitate the breakdown of the highly-structured cellular machinery. Herein, we focus on nitrosative stress signaling, which is intimately associated with endothelial cell injury and blood-brain barrier damage in stroke and neurodegenerative diseases. Unraveling the detrimental role of nitrosative stress signaling in initiating and driving neurovascular pathogenesis may lead to the development of novel vasoprotective strategies via restorative therapies for brain diseases.

Regulation of the ischemia-induced autophagy-lysosome processes by nitrosative stress in endothelial cells.

The cellular mechanisms that underlie the diverse nitrosative stress-mediated cellular events associated with ischemic complications in endothelial cells are not yet clear. To characterize whether autophagic elements are associated with the nitrosative stress that causes endothelial damage after ischemia injury, an in vitro sustained oxygen-glucose deprivation (OGD) and an in vivo microsphere embolism model were used in the present study. Consistent with OGD-induced peroxynitrite formation, a rapid induction of microtubule-associated protein 1 light chain 3 (LC3)-I/II conversion and green fluorescent protein-LC3 puncta accumulation were observed in endothelial cells. The Western blot analyses indicated that OGD induced elevations in lysosome-associated membrane protein 2 and cathepsin B protein levels. Similar results were observed in the microvessel insult model, following occlusion of the microvessels using microsphere injections in rats. Furthermore, cultured endothelial cells treated with peroxynitrite (1-50 µm) exhibited a concentration-dependent change in the pattern of autophagy-lysosome signaling. Intriguingly, OGD-induced autophagy-lysosome processes were attenuated by PEP-19 overexpression and by a small-interfering RNA (siRNA)-mediated knockdown of eNOS. The importance of nitrosative stress in ischemia-induced autophagy-lysosome cascades is further supported by our finding that pharmacological inhibition of nitrosative stress by melatonin partially inhibits the ischemia-induced autophagy-lysosome cascade and the degradation of the tight junction proteins. Taken together, the present results demonstrate that peroxynitrite-mediated nitrosative stress at least partially potentiates autophagy-lysosome signaling during sustained ischemic insult-induced endothelial cell damage.