Relationship between serum endothelin-1 and in-stent restenosis following vertebral artery stenting.

The study objective was to investigate the relations between serum endothelin-1 and in-stent restenosis in vertebral artery stenting. Sixty-eight patients undergoing re-examination of vertebral artery stenting in the Department of Cerebrovascular Disease, Hangzhou Third People's Hospital, between April 2019 and October 2022, were invited to participate. According to the presence of vertebral artery stenting, patients were divided into the restenosis (n = 19) or non-restenosis (n = 49) groups. General clinical data and endothelin-1 levels were compared between the groups. Logistic regression analysis was used to explore the relations between endothelin-1 level and risk for in-stent restenosis. Receiver operating characteristic curves were drawn to test the diagnostic value of serum endothelin-1 level for in-stent restenosis. Compared with the non-restenosis group, restenosis group levels of low-density lipoprotein, triglycerides, and endothelin-1 were significantly higher (p < 0.05) Multivariate logistic regression analysis showed that endothelin-1, stent length, and low-density lipoprotein were independently associated with in-stent restenosis (odds ratio = 1.502, 95% confidence interval: 0.042 ~ 0.212, p = 0.000; odds ratio = 1.899, 95% confidence interval: 1.116 ~ 2.237, p = 0.000; odds ratio = 1.899, 95% confidence interval: 1.228 ~ 3.337, p = 0.001, respectively). Area under the curve for serum endothelin-1 in the diagnosis of vertebral artery in-stent restenosis was 0.938. The best diagnostic cut-off value was 11.94 ng/L. Sensitivity was 89.5%. Specificity was 85.7%. These cumulative data indicate that endothelin-1 level is independently associated with in-stent restenosis.

Delayed recanalization reduced neuronal apoptosis and neurological deficits by enhancing liver-derived trefoil factor 3-mediated neuroprotection via LINGO2/EGFR/Src signaling pathway after middle cerebral artery occlusion in rats.

Delayed recanalization at days or weeks beyond the therapeutic window was shown to improve functional outcomes in acute ischemic stroke (AIS) patients. However, the underlying mechanisms remain unclear. Previous preclinical study reported that trefoil factor 3 (TFF3) was secreted by liver after cerebral ischemia and acted a distant neuroprotective factor. Here, we investigated the liver-derived TFF3-mediated neuroprotective mechanism enhanced by delayed recanalization after AIS. A total of 327 male Sprague-Dawley rats and the model of middle cerebral artery occlusion (MCAO) with permanent occlusion (pMCAO) or with delayed recanalization at 3 d post-occlusion (rMCAO) were used. Partial hepatectomy was performed within 5 min after MCAO. Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 2 (LINGO2) siRNA was administered intracerebroventricularly at 48 h after MCAO. Recombinant rat TFF3 (rr-TFF3, 30 µg/Kg) or recombinant rat epidermal growth factor (rr-EGF, 100 µg/Kg) was administered intranasally at 1 h after recanalization, and EGFR inhibitor Gefitinib (75 mg/Kg) was administered intranasally at 30 min before recanalization. The evaluation of outcomes included neurobehavior, ELISA, western blot and immunofluorescence staining. TFF3 in hepatocytes and serum were upregulated in a similar time-dependent manner after MCAO. Compared to pMCAO, delayed recanalization increased brain TFF3 levels and attenuated brain damage with the reduction in neuronal apoptosis, infarct volume and neurological deficits. Partial hepatectomy reduced TFF3 levels in serum and ipsilateral brain hemisphere, and abolished the benefits of delayed recanalization on neuronal apoptosis and neurobehavioral deficits in rMCAO rats. Intranasal rrTFF3 treatment reversed the changes associated with partial hepatectomy. Delayed recanalization after MCAO increased the co-immunoprecipitation of TFF3 and LINGO2, as well as expressions of p-EGFR, p-Src and Bcl-2 in the brain. LINGO2 siRNA knockdown or EGFR inhibitor reversed the effects of delayed recanalization on apoptosis and brain expressions of LINGO2, p-EGFR, p-Src and Bcl-2 in rMCAO rats. EGFR activator abolished the deleterious effects of LINGO2 siRNA. In conclusion, our investigation demonstrated for the first time that delayed recanalization may enhance the entry of liver-derived TFF3 into ischemic brain upon restoring blood flow after MCAO, which attenuated neuronal apoptosis and neurological deficits at least in part via activating LINGO2/EGFR/Src pathway.

The impact of thrombus surface morphology of the basilar artery on the successful rate of mechanical thrombectomy.

Objective: The present study aimed to investigate the impact of angiographic thrombus surface morphology on the angiographic and clinical outcomes of basilar artery occlusion (BAO). Methods: This retrospective study included 141 patients with acute BAO who underwent mechanical thrombectomy (MT). We categorized thrombus surface phenotypes as either regular (smooth and straight, either convex or concave) or irregular. Patients with BAO were grouped based on the presence of a regular or irregular phenotype, and we compared their angiographic and clinical outcomes. Results: In total, 52.5% (74/141) of acute BAO patients exhibited a regular thrombus morphology. These patients had a higher rate of first-pass effect (28.4% vs. 4.5%, p = 0.0002) and fewer retrieval attempts (2 vs. 2; p = 0.0198) compared to those with irregular morphology. Among patients treated with contact aspiration (CA), the regular thrombus morphology showed a higher first-pass success rate (45.7% vs. 12.8%; p = 0.0017), a shorter procedural duration (46 vs. 50 min; p = 0.0159), and fewer retrieval attempts (1 vs. 2; p = 0.0338) compared to stent retriever (SR) thrombectomy. Both the regular thrombus morphology (OR 7.72, 95% CI 2.02-29.52; p = 0.003) and using CA as the first-line treatment (OR 3.37, 95% CI 1.12-10.13; p = 0.031) independently predicted first-pass success. Conclusion: For BAO patients treated with CA as the primary strategy, the presence of a regular thrombus surface might predict higher first-pass success and shorter procedural duration. A diligent assessment of thrombus morphology within the MT workflow could improve the feasibility of procedural techniques.

A Novel Compound Heterozygous Gene Mutation of Dolichol Kinase Deficiency (DOLK-CDG).

BACKGROUND: Congenital disorder of glycosylation caused by mutation of the DOLK(DOLK-CDG) is a group of rare autosomal recessive diseases with an early-onset age and poor prognosis. DOLK-CDG can cause the dysfunction of multiple systems and organs such as the heart, skin, nerves, and bones. CASE PRESENTATION: We report a child with DOLK-CDG diagnosed and treated in the Affiliated Hospital of Qingdao University. The child was born with neonatal asphyxia, Ichthyoid rash, and congenital heart disease. His fingers of both the hands looked like lotus roots, and the palm and foot were covered by a white membrane. He was hospitalized with a severe infection at 4 months after birth. Physical examination showed that he was complicated with development delay and hypotonia. He experienced convulsions 1 hour after admission and died of multiple organ failure 2 hours after admission. Blood samples were taken for genetic testing before the child died. The results showed that there was a novel compound heterozygous mutation in DOLK, c.1268C>G (P.P423R) and c.1581_1583del (P.527_528del). CONCLUSION: This mutation is new and not included in the human gene mutation library. The discovery of the novel mutation broadened the mutation spectrum of DOLK. At the same time, we sorted out the DOLK-CDG gene mutation sites and related clinical manifestations reported by August 2021 through a literature review.

Case report: genetic analysis of a child with 18q deletion syndrome and developmental dysplasia of the hip.

OBJECTIVE: To analyze the genotypes and phenotypes of a child with developmental dysplasia of the hip (DDH), developmental delays, recurrent fever, hypothyroidism and cleft palate. METHODS: G-banding karyotyping analysis and next-generation sequencing (NGS) were performed for the patient. The genotypes of the parents of the patient were verified by copy number variation analysis and Sanger sequencing to determine the source of variations. RESULTS: The karyotype of the patient was 46, XX. A 10.44 Mb deletion (chr18:67562936-78005270del) at 18q22.2q23 was found by NGS. We identified 2 HSPG2 mutations (chr1: 22206699, c.2244C > A, exon 17, p.H748Q; chr1: 22157321-22157321, c.11671 + 154insA, intron). One mutation was inherited from the father, and the other was inherited from the mother. CONCLUSION: This is the first 18q deletion syndrome case accompanied by DDH. Most phenotypes of this patient, such as developmental delays and cleft palate, may be related to the 18q22.2q23 deletion, but no variants in genes related to DDH were found in this deletion region. DDH may be related to mutations of HSPG2.

CT-Based Radiomics Nomogram Improves Risk Stratification and Prediction of Early Recurrence in Hepatocellular Carcinoma After Partial Hepatectomy.

Objectives: To develop and validate an intuitive computed tomography (CT)-based radiomics nomogram for the prediction and risk stratification of early recurrence (ER) in hepatocellular carcinoma (HCC) patients after partial hepatectomy. Methods: A total of 132 HCC patients treated with partial hepatectomy were retrospectively enrolled and assigned to training and test sets. Least absolute shrinkage and selection operator and gradient boosting decision tree were used to extract quantitative radiomics features from preoperative contrast-enhanced CT images of the HCC patients. The radiomics features with predictive value for ER were used, either alone or in combination with other predictive features, to construct predictive models. The best performing model was then selected to develop an intuitive, simple-to-use nomogram, and its performance in the prediction and risk stratification of ER was evaluated using the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). Results: The radiomics model based on the radiomics score (Rad-score) achieved AUCs of 0.870 and 0.890 in the training and test sets, respectively. Among the six predictive models, the combined model based on the Rad-score, Edmondson grade, and tumor size had the highest AUCs of 0.907 in the training set and 0.948 in the test set and was used to develop an intuitive nomogram. Notably, the calibration curve and DCA for the nomogram showed good calibration and clinical application. Moreover, the risk of ER was significantly different between the high- and low-risk groups stratified by the nomogram (p <0.001). Conclusions: The CT-based radiomics nomogram developed in this study exhibits outstanding performance for ER prediction and risk stratification. As such, this intuitive nomogram holds promise as a more effective and user-friendly tool in predicting ER for HCC patients after partial hepatectomy.

BMS-470539 Attenuates Oxidative Stress and Neuronal Apoptosis via MC1R/cAMP/PKA/Nurr1 Signaling Pathway in a Neonatal Hypoxic-Ischemic Rat Model.

Neuronal apoptosis induced by oxidative stress plays an important role in the pathogenesis and progression of hypoxic-ischemic encephalopathy (HIE). Previous studies reported that activation of melanocortin-1 receptor (MC1R) exerts antioxidative stress, antiapoptotic, and neuroprotective effects in various neurological diseases. However, whether MC1R activation can attenuate oxidative stress and neuronal apoptosis after hypoxic-ischemic- (HI-) induced brain injury remains unknown. Herein, we have investigated the role of MC1R activation with BMS-470539 in attenuating oxidative stress and neuronal apoptosis induced by HI and the underlying mechanisms. 159 ten-day-old unsexed Sprague-Dawley rat pups were used. HI was induced by right common carotid artery ligation followed by 2.5 h of hypoxia. The novel-selective MC1R agonist BMS-470539 was administered intranasally at 1 h after HI induction. MC1R CRISPR KO plasmid and Nurr1 CRISPR KO plasmid were administered intracerebroventricularly at 48 h before HI induction. Percent brain infarct area, short-term neurobehavioral tests, Western blot, immunofluorescence staining, Fluoro-Jade C staining, and MitoSox Staining were performed. We found that the expression of MC1R and Nurr1 increased, peaking at 48 h post-HI. MC1R and Nurr1 were expressed on neurons at 48 h post-HI. BMS-470539 administration significantly attenuated short-term neurological deficits and infarct area, accompanied by a reduction in cleaved caspase-3-positive neurons at 48 h post-HI. Moreover, BMS-470539 administration significantly upregulated the expression of MC1R, cAMP, p-PKA, Nurr1, HO-1, and Bcl-2. However, it downregulated the expression of 4-HNE and Bax, as well as reduced FJC-positive cells, MitoSox-positive cells, and 8-OHdG-positive cells at 48 h post-HI. MC1R CRISPR and Nurr1 CRISPR abolished the antioxidative stress, antiapoptotic, and neuroprotective effects of BMS-470539. In conclusion, our findings demonstrated that BMS-470539 administration attenuated oxidative stress and neuronal apoptosis and improved neurological deficits in a neonatal HI rat model, partially via the MC1R/cAMP/PKA/Nurr1 signaling pathway. Early administration of BMS-470539 may be a novel therapeutic strategy for infants with HIE.

Activation of MC1R with BMS-470539 attenuates neuroinflammation via cAMP/PKA/Nurr1 pathway after neonatal hypoxic-ischemic brain injury in rats.

BACKGROUND: Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of hypoxic-ischemic (HI)-induced brain injury. Activation of melanocortin-1 receptor (MC1R) has been shown to exert anti-inflammatory and neuroprotective effects in several neurological diseases. In the present study, we have explored the role of MC1R activation on neuroinflammation and the potential underlying mechanisms after neonatal hypoxic-ischemic brain injury in rats. METHODS: A total of 169 post-natal day 10 unsexed rat pups were used. HI was induced by right common carotid artery ligation followed by 2.5 h of hypoxia. BMS-470539, a specific selective MC1R agonist, was administered intranasally at 1 h after HI induction. To elucidate the potential underlying mechanism, MC1R CRISPR KO plasmid or Nurr1 CRISPR KO plasmid was administered via intracerebroventricular injection at 48 h before HI induction. Percent brain infarct area, short- and long-term neurobehavioral tests, Nissl staining, immunofluorescence staining, and Western blot were conducted. RESULTS: The expression levels of MC1R and Nurr1 increased over time post-HI. MC1R and Nurr1 were expressed on microglia at 48 h post-HI. Activation of MC1R with BMS-470539 significantly reduced the percent infarct area, brain atrophy, and inflammation, and improved short- and long-term neurological deficits at 48 h and 28 days post-HI. MC1R activation increased the expression of CD206 (a microglial M2 marker) and reduced the expression of MPO. Moreover, activation of MC1R with BMS-470539 significantly increased the expression levels of MC1R, cAMP, p-PKA, and Nurr1, while downregulating the expression of pro-inflammatory cytokines (TNFα, IL-6, and IL-1ß) at 48 h post-HI. However, knockout of MC1R or Nurr1 by specific CRISPR reversed the neuroprotective effects of MC1R activation post-HI. CONCLUSIONS: Our study demonstrated that activation of MC1R with BMS-470539 attenuated neuroinflammation, and improved neurological deficits after neonatal hypoxic-ischemic brain injury in rats. Such anti-inflammatory and neuroprotective effects were mediated, at least in part, via the cAMP/PKA/Nurr1 signaling pathway. Therefore, MC1R activation might be a promising therapeutic target for infants with hypoxic-ischemic encephalopathy (HIE).

Genetic Analysis of Gitelman Syndrome: Co-existence with Hyperthyroidism in a Two-year-old Boy.

CASE PRESENTATION: A two-year-old boy visited the doctor for hypokalemia and metabolic alkalosis. Laboratory examination revealed that urinary potassium excretion and serum aldosterone level were increased, with hyperthyroidism and thyroid-related antibodies positive at the same time. Genetic testing showed that there was a complex heterozygous mutation in the SLC12A3 gene, c.1077C>G (p.N359K) and c.1567G>A (p.A523?); the final diagnosis was Gitelman syndrome and autoimmune hyperthyroidism. BACKGROUND: Gitelman syndrome is an autosomal recessive genetic disease caused by the inactivation of mutation of the SLC12A3 gene. The onset age is more than 6 years old; it is mainly manifested as low blood potassium, low blood sodium, low blood chlorine, metabolic alkalosis, increased urine potassium and urine chlorine excretion, and low urine calcium. Autoimmune hyperthyroidism manifests due to autoimmune disorders. The highest incidence rate in children is of Graves' disease, followed by chronic lymphocytic thyroiditis. CONCLUSION: Several cases of Gitelman syndrome with autoimmune hyperthyroidism have been reported, most of which were Asian adults, and the case we identified is the first reported case in children under 14 years with both Gitelman syndrome and autoimmune hyperthyroidism. At the same time, we carried out a high-precision clinical exosome analysis of the gene of this case and further explored the relationship between Gitelman syndrome and autoimmune hyperthyroidism from the perspective of the gene.This case suggests that even children under 6 years with hyperthyroidism and hypokalemia should be suspected of Gitelman syndrome to avoid misdiagnosis.

microRNA-448 inhibits stemness maintenance and self-renewal of hepatocellular carcinoma stem cells through the MAGEA6-mediated AMPK signaling pathway.

Hepatocellular carcinoma (HCC) occurs mainly in patients with chronic liver disease and cirrhosis. Increasing evidence has identified the involvement of microRNAs (miRNAs) acting as essential regulators in the progression of HCC. As predicted by microarray analysis, miR-448 might potentially affect HCC progression by regulating the melanoma-associated antigen (MAGEA). Therefore, the present investigation focused on exploring whether or not miR-448 and MAGEA6 were involved in the self-renewal and stemness maintenance of HCC stem cells. The interaction among miR-448, MAGEA6, and the AMPK signaling pathway was evaluated. It was noted that miR-448 targeted and downregulated MAGEA6, thus activating the AMP-activated protein kinase (AMPK) signaling pathway in HCC. Furthermore, for the purpose of exploring the functional relevance of MAGEA6 and miR-448 on the sphere formation, colony formation, and invasion and migration of HCC stem cells, the CD133+ CD44 + HCC stem cells were sorted and treated with the mimic or inhibitor of miR-448, small interfering RNA (siRNA) against MAGEA6 or an AMPK activator AICAR. MAGEA6 silencing or miR-448 overexpression was demonstrated to inhibit the abilities of sphere formation, colony formation, cell migration, and invasion of HCC cells. Afterwards, a rescue experiment was conducted and revealed that MAGEA6 silencing reversed the effects of miR-448 inhibitor on stemness maintenance and self-renewal of HCC stem cells. Finally, after the in vivo experiment was carried out, miR-448 was observed to restrain the tumor formation and stemness in vivo. Altogether, miR-448 activates the AMPK signaling pathway by downregulating MAGEA6, thus inhibiting the stemness maintenance and self-renewal of HCC stem cells, which identifies miR-448 as a new therapeutic strategy for HCC.

Post-traumatic stress disorder after typhoon disaster and its correlation with platelet 5-HT concentrations.

OBJECTIVE: To investigate residents' psychological stress factors and research the correlation between post-traumatic stress disorder (PTSD) and platelet 5-HT concentrations so as to provide scientific bases for diagnosis and treatment of PTSD and psychological intervention for people in the disaster area. METHODS: A questionnaire survey of 5500 residents who have accepted psychological help was conducted by the emphatic investigation method. While high performance liquid chromatography was used to detect the platelet serotonin concentration of 100 PTSD patients and 100 healthy people. RESULTS: (1) Of the 5114 cases, 3167 (61.93%) showed positive results in screening for psychological stress symptoms, and 399 (7.8%) were tested having apparent PTSD symptoms. Male and female prevalence showed no significant difference (χ(2) = -0.380, P = 0.704). The differences of prevalence between different age groups were statistically significant (χ(2) = 381.89, P = 0.000). (2) The differences in the level of platelet 5-HT between PTSD patients and normal control group were statistically significant. CONCLUSIONS: The typhoon of Hainan Province caused relatively large psychological problems to the disaster victims. Compared with normal control group, the platelet 5-HT levels of PTSD patients in the disaster areas are lower. It may be related to incidents exposure levels, cultural background, religious ideas, social concerns and psychological rescue of the residents who live in the disaster areas of Hainan.