[Association between congenital hypothyroidism and in-hospital adverse outcomes in very low birth weight infants].

Objective: To investigate the association between congenital hypothyroidism (CH) and the adverse outcomes during hospitalization in very low birth weight infants (VLBWI). Methods: This prospective, multicenter observational cohort study was conducted based on the data from the Sino-northern Neonatal Network (SNN). Data of 5 818 VLBWI with birth weight <1 500 g and gestational age between 24-<37 weeks that were admitted to the 37 neonatal intensive care units from January 1st, 2019 to December 31st, 2022 were collected and analyzed. Thyroid function was first screened at 7 to 10 days after birth, followed by weekly tests within the first 4 weeks, and retested at 36 weeks of corrected gestational age or before discharge. The VLBWI were assigned to the CH group or non-CH group. Chi-square test, Fisher exact probability method, Wilcoxon rank sum test, univariate and multivariate Logistic regression were used to analyze the relationship between CH and poor prognosis during hospitalization in VLBWI. Results: A total of 5 818 eligible VLBWI were enrolled, with 2 982 (51.3%) males and the gestational age of 30 (29, 31) weeks. The incidence of CH was 5.5% (319 VLBWI). Among the CH group, only 121 VLBWI (37.9%) were diagnosed at the first screening. Univariate Logistic regression analysis showed that CH was associated with increased incidence of extrauterine growth retardation (EUGR) (OR=1.31(1.04-1.64), P<0.05) and retinopathy of prematurity (ROP) of stage Ⅲ and above (OR=1.74(1.11-2.75), P<0.05). However, multivariate Logistic regression analysis showed no significant correlation between CH and EUGR, moderate to severe bronchopulmonary dysplasia, grade Ⅲ to Ⅳ intraventricular hemorrhage, neonatal necrotizing enterocolitis in stage Ⅱ or above, and ROP in stage Ⅲ or above (OR=1.04 (0.81-1.33), 0.79 (0.54-1.15), 1.15 (0.58-2.26), 1.43 (0.81-2.53), 1.12 (0.70-1.80), all P>0.05). Conclusion: There is no significant correlation between CH and in-hospital adverse outcomes, possibly due to timely diagnosis and active replacement therapy.

[Mechanism of high frequency rTMS on cognitive function in cerebral ischemic rats based on RNA sequencing].

Objective: To clarify the effect of high-frequency repetitive transcranial magnetic stimulation (rTMS) on cognitive function in cerebral ischemic rats, and to explore its underlying mechanism by RNA sequencing. Methods: Thirty male Sprague-Dawley (SD) rats underwent transient middle cerebral artery occlusion (tMCAO). According to the Bederson score, 10 rats with a score of 1-3 were excluded, and the remaining 20 rats were then randomly divided into the tMCAO group (n=10) and the rTMS group (n=10). Meanwhile, 10 rats with sham operation were assigned to the sham group (n=10). Rats in the rTMS group received 20 Hz rTMS from day 7 to day 28 after surgery. From day 28 to day 33 after the operation, Morris water maze test was performed to detect the cognitive function of rats in each group. The cortical tissues around the infarcts from the rTMS tMCAO groups were taken for RNA sequencing analysis, with 3 rats in each group. Results: The escape latency of rats in the rTMS group[ (53±4)s] and the group [(51±5)s] were significantly shorter than that of the tMCAO group[ (58±4)s, P<0.05)]. The times that the rats crossed the original platform in 60 seconds in the rTMS group[2.5 (1.5-3.0)] and sham group[3.0 (1.5-3.0)] were more than that of the tMCAO group [1.0(0.5-1.5)] (P<0.05). RNA sequencing detected 16 significantly differentially expressed genes, including 9 up-regulated genes and 7 down-regulated genes. GO analysis showed that the functions of up-regulated genes were mainly concentrated in the processes of chemical homeostasis and cell metal ion homeostasis. While the functions of down-regulated genes mainly enriched in the inflammatory response. Conclusion: Twenty Hz rTMS can improve the cognitive function of rats with cerebral infarction, and its underlying mechanism may be related to maintaining chemical and metal ion homeostasis and regulating the polarization of microglia to reduce neuroinflammation.

Seasonal concentrations, contamination levels, and health risk assessment of arsenic and heavy metals in the suspended particulate matter from an urban household environment in a metropolitan city, Beijing, China.

The levels and health risks of arsenic and heavy metals (As, Ba, Cd, Co, Cr, Cu, Mn, Ni, Pb, and Zn) in the suspended particulate matter (SPM) collected from an urban household environment in Beijing of China for 12 months were investigated. The mean concentrations of the studied toxic elements were higher and lower than crustal abundance and PM2.5 in the urban outdoors of Beijing. The concentrations of the studied elements displayed significant seasonality. The highest concentrations of the total elements occurred in winter, followed by autumn, while the lowest concentrations were recorded in summer. Based on the calculated values of enrichment factor (EF) and geoaccumulation index (Igeo), the levels for As and Cu were heavily contaminated, while those for Cd, Pb, and Zn were extremely contaminated. As and Pb might pose risks to children and adults via ingestion exposure. The accumulative risks of multi-elements resulted from dermal contact and inhalation exposures were not negligible. More attention should be paid to reducing the non-carcinogenic and carcinogenic health risks posed by the toxic elements bound to urban household SPM particles via ingestion, inhalation, and dermal contact exposure.

Scaffold evaluation of liguzinediol analogs as novel cardiotonic agents.

Liguzinediol (LZDO) could mediate the positive inotropic effects through sarcoplasmic reticulum Ca2+ ATPase-dependent mechanism without the risk of arrhythmia. However, the pharmacophore of LZDO contributed to the activities was not clear. The aim of this work was to explore the relationship between positive inotropic effect and scaffold of LZDO as well as to check whether the pharmacophore of LZDO on anti-heart failure activity was located at the pyrazine ring. A series of LZDO analogs (3a-b, 4a-b, 9-19) were designed and synthesised, and their activities were evaluated on isolated heart contractility by Langendorff perfusion. The results showed that the efficacy of LZDO was reduced when the hydroxyl, carboxyl or ester moieties at the side chain position of LZDO were induced, and the para-dihydroxy in LZDO was necessary for its activity. Thus, the pharmacophore of the positive inotropic effect might be located at the whole scaffold of LZDO, but not at the pyrazine ring. The finding may provide an important clue of the pharmacophore for the development of novel cardiotonic agents.

The ubiquitin ligase F-box/G-domain protein 1 promotes the degradation of the disease-linked protein torsinA through the ubiquitin-proteasome pathway and macroautophagy.

DYT1 dystonia is a dominantly inherited, disabling neurological disorder with low penetrance that is caused by the deletion of a glutamic acid (ΔE) in the protein torsinA. We previously showed that torsinA(wt) is degraded through macroautophagy while torsinA(ΔE) is targeted to the ubiquitin-proteasome pathway (UPP). The different catabolism of torsinA(wt) and (ΔE) potentially modulates torsinA(wt):torsinA(ΔE) stoichiometry. Therefore, gaining a mechanistic understanding on how the protein quality control machinery clears torsinA(ΔE) in neurons may uncover important regulatory steps in disease pathogenesis. Here, we asked whether F-box/G-domain protein 1 (FBG1), a ubiquitin ligase known to degrade neuronal glycoproteins, is implicated in the degradation of torsinA(ΔE) by the UPP. In a first set of studies completed in cultured cells, we show that FBG1 interacts with and influences the steady-state levels of torsinA(wt) and (ΔE). Interestingly, FBG1 achieves this effect promoting the degradation of torsinA not only through the UPP, but also by macroautophagy. To determine the potential clinical significance of these findings, we asked if eliminating expression of Fbg1 triggers a motor phenotype in torsinA(ΔE) knock in (KI) mice, a model of non-manifesting DYT1 mutation carriers. We detected differences in spontaneous locomotion between aged torsinA(ΔE) KI-Fbg1 knock out and control mice. Furthermore, neuronal levels of torsinA were unaltered in Fbg1 null mice, indicating that redundant systems likely compensate in vivo for the absence of this ubiquitin ligase. In summary, our studies support a non-essential role for FBG1 on the degradation of torsinA and uncover a novel link of FBG1 to the autophagy pathway.

Apolipoprotein E epsilon4 allele is associated with the volume of white matter changes in patients with lacunar infarcts.

The relationship between the apolipoprotein E (APOE) exon 4 polymorphism and white matter changes (WMC) in elderly subjects or patients with Alzheimer's disease is controversial. To investigate this polymorphism in relation to WMC in patients with lacunar infarcts, we prospectively observed 67 patients with acute lacunar infarct and 134 age- and sex-matched controls. Genotypes were determined using a nested polymerase chain reaction. WMC were measured quantitatively and were divided into two groups, severe and mild, with the mean volume of WMC as the cut point. Twenty-two patients (33%) had severe WMC. There was a significant difference in the distribution of APOE epsilon2, epsilon3, and epsilon4 alleles between severe and mild WMC groups (P = 0.002). The frequency of epsilon4 alleles was higher in patients with severe WMC than in those with mild WMC (25% vs. 7%, P = 0.003). These results suggest that APOE epsilon4 may exacerbate WMC in patients with lacunar infarcts. Further studies are required to confirm this finding.

Multiple acute cerebral infarcts on diffusion-weighted imaging and risk of recurrent stroke.

Multiple acute cerebral infarcts (MACIs) detected by diffusion-weighted imaging (DWI) may indicate an unstable source of thromboembolism. The authors studied 119 consecutive acute ischemic stroke patients within 24 hours of onset with DWI. MACIs were present in 20 patients (16.8%). During the follow-up period, there were 15 recurrent strokes, 3 acute coronary syndromes, and 5 deaths. MACI was the only significant independent predictor for vascular events and death (odd ratio [OR]] = 4.34; p = 0.001) and stroke recurrence (OR = 5.93; p = 0.001).