ObjectiveTo investigate the mechanism by which Feixin decoction treats hypoxic pulmonary hypertension （HPH） by regulating the peroxisome proliferator-activated receptor gamma （PPARγ）/nuclear factor-kappa B （NF-κB）/NOD-like receptor pyrin domain containing 3 （NLRP3） signaling pathway. MethodsForty-eight male SD rats were randomly allocated into normal， hypoxia， and low-， medium- and high-dose （5.85， 11.7， 23.4 g·kg^-1， respectively） Feixin decoction groups， with 8 rats in each group. Except the normal group， the remaining five groups were placed in a hypoxia chamber with an oxygen concentration of （10.0±0.5）% for 8 h per day， 28 days， and administrated with corresponding drugs during the modeling process. After 4 weeks of treatment， echocardiographic parameters ［pulmonary artery acceleration time （PAT）， pulmonary artery ejection time （PET）， right ventricular anterior wall thickness （RVAWd）， and tricuspid annular plane systolic excursion （TAPSE）］ were measured for each group. The right ventricular systolic pressure （RVSP） was measured by the right heart catheterization method， and the right ventricular hypertrophy index （RVHI） was calculated by weighing the heart. The pathological changes in pulmonary arterioles were observed by hematoxylin-eosin staining. The co-localization of α-smooth muscle actin （α-SMA） with NLRP3， N-terminal gasdermin D （N-GSDMD）， and cysteinyl aspartate-specific proteinase-1 （Caspase-1） in pulmonary arteries was detected by immunofluorescence. The protein levels of PPARγ， NF-κB， NLRP3， apoptosis-associated speck-like protein containing a CARD （ASC）， N-GSDMD， interleukin-1β （IL-1β）， interleukin-18（IL-18）， and cleaved Caspase-1 in the lung tissue was determined by Western blot. The ultrastructural changes in pulmonary artery smooth muscle cells （PASMCs） were observed by transmission electron microscopy. ResultsCompared with the normal group， the hypoxia group showed increased RVSP and RVHI （P<0.01）， decreased right heart function （P<0.01）， increased pulmonary vascular remodeling （P<0.01）， increased co-localization of α-SMA with NLRP3， N-GSDMD， and Caspase-1 in pulmonary arterioles （P<0.01）， up-regulated protein levels of NF-κB， NLRP3， ASC， N-GSDMD， IL-1β， IL-18， and cleaved Caspase-1 in the lung tissue （P<0.05， P<0.01）， a down-regulated protein level of PPARγ （P<0.05， P<0.01）， and pyroptosis in PASMCs. Compared with the hypoxia group， Feixin decoction reduced RVSP and RVHI， improved the right heart function and ameliorated pulmonary vascular remodeling （P<0.05， P<0.01）， decreased the co-localization of α-SMA with NLRP3， N-GSDMD， and Caspase-1 （P<0.05， P<0.01）， down-regulated the protein levels of NF-κB， NLRP3， ASC， N-GSDMD， IL-1β， IL-18， and cleaved Caspase-1 in the lung tissue （P<0.05， P<0.01）， up-regulated the protein level of PPARγ （P<0.05， P<0.01）， and alleviated pyroptosis in PASMCs. ConclusionFeixin decoction can ameliorate pulmonary vascular remodeling and right heart dysfunction in chronically induced HPH rats by regulating pyroptosis in PASMCs through the PPARγ/NF-κB/NLRP3 pathway.

Objective:To explore the reasonable timing of radiotherapy for epidermal growth factor receptor ( EGFR) mutation-positive non-small cell lung cancer patients with brain metastasis in the era of third-generation targeted drugs. Methods:Clinical data of EGFR mutation-positive non-small cell lung cancer patients with brain metastasis who received first-line treatment with third-generation targeted drugs and stereotactic radiotherapy at Shanghai Armed Police Corps Hospital from September 2019 to May 2022 were retrospectively analyzed. According to the timing of radiotherapy before / after targeted drug resistance, all patients were divided into the early and salvage radiotherapy groups. The proportion of brain metastasis, physical fitness, complete response rate, objective response rate, delaying the progression of brain metastasis and overall survival (OS) were compared between two groups. Kaplan-Meier method was used for survival analysis, log-rank test was used for univariate prognostic analysis, and factors with P <0.1 were included in Cox multivariate analysis. Results:A total of 85 patients were included, including 51 (60%) cases receiving early radiotherapy. Patients who participated in early radiotherapy had a higher proportion of symptomatic brain metastasis (82% vs. 56%, P=0.013) and poorer physical fitness (Kanofsky performance score <70: 61% vs. 26%, P=0.002) compared to patients who underwent salvage radiotherapy. Early radiotherapy significantly improved the complete response rate of intracranial lesions (35% vs. 12%, P=0.015) and objective response rate (88% vs. 71%, P=0.041), delayed the progression of brain metastasis (median intracranial progression free survival: 23.0 months vs. 16.0 months, P=0.005; median intracranial secondary progression free survival: 31.0 months vs. 22.0 months, P=0.021), and improved OS (median OS: 44.0 months vs. 35.0 months, P=0.046). In multivariate analysis, diagnosis-specific graded prognostic assessment score <2.5, mutation of EGFR exon 21, and salvage brain radiotherapy were adverse prognostic factors for OS. Conclusion:In the era of third-generation targeted drugs therapy, early involvement of stereotactic radiotherapy in non-small cell lung cancer patients with brain metastasis can bring greater clinical benefits.

We retrospectively analyzed the clinical data of seven patients (four men and three women) with primary hyperoxaluria (PH) type 1 (PH1) in the Department of Nephrology of Zhongda Hospital, Southeast University from January 2018 to October 2023. The mean age at disease onset was 32.1 (range: 26-42) years. The mean age at diagnosis was 40.6 (range: 28-51) years. All patients initially had kidney stones, and three patients were found to have renal insufficiency at the time of disease onset. Among them, two patients underwent hemodialysis immediately. Symptoms at the first visit included bone pain ( n=7), joint pain or deformity ( n=5), fatigue ( n=5), hypotension ( n=3), and subcutaneous nodules ( n=2). Four patients had a family history of PH. All patients had varying degrees of anemia (60-114 g/L), significant hypoalbuminemia (16.5-32.1 g/L), and hypercoagulable state (D-dimer: 2 230-12 781 μg/L). Seven patients received maintenance hemodialysis; their mean age was 37.7 (range: 26-50) years. The mean duration from disease onset to hemodialysis was 5.6 (range: 0-20) years. Five patients repeatedly experienced dialysis access dysfunction. Three patients underwent kidney transplantation before a diagnosis was made, and all transplanted kidneys lost function due to oxalate deposition. The mean follow-up duration was 14.43 (range: 4-38) months. Unfortunately, one patient died. All seven patients underwent computed tomography of the abdomen. All patients suffered skeletal abnormalities, bilateral nephrolithiasis, and nephrocalcinosis. Six patients carried AGXT gene mutations, including four compound heterozygous mutations and two pure homozygous mutations.The mutation sites included: c.823-824dup.AG (p.S275Rfs*38)(exon 8), c.815-816ins.GA (p.S275Rfs*38)(exon 8), c.595G>A (p.G199S) (exon 5), c.32C>G (p.P11R) (exon 1), and c.638C>T (p.A213V)(exon 6). According to the American College of Medical Genetics and Genomics guidelines, two loci were identified as likely pathogenic variants, seven were identified as pathogenic variants, and one locus was identified as having uncertain significance. In addition, patients 1 and 4 underwent skin biopsy, patient 2 underwent renal transplant biopsy, and patient 3 underwent bone marrow biopsy. Interestingly, significant oxalate deposition was found in the tissues. Therefore, PH1 is a rare autosomal recessive inherited disease. This study not only enhanced the understanding of the clinical characteristics of PH1 patients but also had great significance in early diagnosis and treatment of the disease.

The effect of anti-programmed cell death 1 (anti-PD-1) immunotherapy is limited in patients with hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP1) expression increased in liver tumor cells in early HCC, and Akkermansia muciniphila abundance decreased in the colon. The response to anti-PD-1 treatment is associated with A. muciniphila abundance in many tumors. However, the interaction between A. muciniphila abundance and YAP1 expression remains unclear in HCC. Here, anti-PD-1 treatment decreased A. muciniphila abundance in the colon, but increased YAP1 expression in the tumor cells by mice with liver tumors in situ. Mechanistically, hepatocyte-specific Yap1 knockout (Yap1^LKO) maintained bile acid homeostasis in the liver, resulting in an increased abundance of A. muciniphila in the colon. Yap1 knockout enhanced anti-PD-1 efficacy. Therefore, YAP1 inhibition is a potential target for increasing A. muciniphila abundance to promote anti-PD-1 efficacy in liver tumors. Dihydroartemisinin (DHA), acting as YAP1 inhibitor, increased A. muciniphila abundance to sensitize anti-PD-1 therapy. A. muciniphila by gavage increased the number and activation of CD8⁺ T cells in liver tumor niches during DHA treatment or combination with anti-PD-1. Our findings suggested that the combination anti-PD-1 with DHA is an effective strategy for liver tumor treatment.

Objective:To summarize the clinical characteristics and genetic features of tyrosine hydroxylase deficiency(THD) caused by TH gene variants for the improvement of the understanding of the disease. Methods:The clinical and genetic data of 33 children with THD caused by TH gene variants were diagnosed in the Department of Neurology of Beijing Children′s Hospital, Capital Medical University from May 2011 to January 2020 and their data were retrospectively collected and analyzed. Results:There were 19 females and 14 males.The age at onset was ranged from 0 to 6.3 years.13 patients developed diseases, accompanied with fever after infection, and 1 patient suffered from hypoxia, 19 patients suffered from no predisposing factors.There were 7 mild TH-deficient dopa-responsive dystonia cases, 16 severe TH-deficient infantile parkinsonism with motor delay cases and 10 very severe TH-deficient progressive infantile encephalopathy cases.Clinical symptoms were fluctuating, including 26 cases of diurnal fluctuation, 22 cases of infection aggravation, and 30 cases of fatigue aggravation.The initial symptoms included tiptoeing and numbness in the limbs(7 cases), motor development retardation or degression (26 cases), fremitus (8 cases), ptosis (2 cases), and status dystonicus (3 cases). Other clinical features had hypermyotonia (23 cases), hypomyotonia (27 cases), decreased movement (27 cases), decreased facial expression (24 cases), fremitus (18 cases), tiptoeing (20 cases), talipes equinovarus (7 cases), ptosis (8 cases), oculogyric crisis (10 cases), salivation (21 cases), dysphagia (12 cases), dysarthria (16 cases), dyspnea (3 cases), increased sleep (10 cases), decreased sleep (5 cases), irritable mood (15 cases), apathetic mood (2 cases), profuse sweating (8 cases), and status dystonicus (6 cases). A total of 6 patients′ right limbs were more severe, and 14 patients′ lower limbs were more severe.Eight patients had family history, and Levodopa treatment was effective for all patients.Ten patients suffered side effects, including dyskinesia and irritability.Four patients were lost follow-up, and 29 patients were followed up between 0.8 and 13.2 years old until Ja-nuary 2020.Totally, 22 patients almost had no such symptoms.Twenty-five TH gene pathogenic variants were discovered in 33 patients.There were 13 novel variants (c.1160T>C, c.1303T>C, c.887G>A, c.1084G>A, c.1097A>T, c.734G>T, c.907C>G, c.588G>T, c.992T>G, c.755G>A, c.184-6C>T, c.1510C>T, c.910G>A) and 2 patients had c. 910G>A variant.Meanwhile, there were 5 hot variants [c.698G>A(13 cases), c.457C>T(9 cases), c.739G>A(6 cases), c.1481C>T(4 cases), c.694C>T(3 cases)]. c.910G>A(2 cases) may be the foun-der variant of Chinese population. Conclusions:THD caused by TH gene variant mostly onsets from infant, with complex clinical features.Most of these patients were severe, and only a few were very severe and mild.Very severe and mild symptoms were easily misdiagnosed.Levodopa treatment was obviously effective.A possible founder variant of Chinese population (c.910G>A) was found.c.698G>A and c. 457C>T mutations mainly appeared in patients with severe and extremely severe THD, while c. 739G>A mainly appeared in patients with mild THD.

Objective:To summarize the clinical data of patients with acute pandysautonomia (APD) and discuss the treatment and prognosis of them.Methods:A total of 13 patients with APD in the Department of Neurology, Beijing Children′s Hospital, Capital Medical University, from January 2010 to December 2019, were investigated retrospectively.The general data, clinical symptoms, autonomic nerve examination and function test, laboratory examination, treatment and follow-up were collected and analyzed.Results:There were 4 males and 9 females in 13 patients with APD, with an average age was 8 years and 5 months (3 years and 8 months to 12 years and 5 months ). The average course of disease was 94.5 d (14-410 d). The common initial symptoms were gastrointestinal motility disorder (11 cases), dysuria (3 cases), and upright syncope/vertigo (3 cases). During the course of the disease, all the patients manifested with gastrointestinal motility disfunction and dyshidrosis, glands involvement and orthostatic hypotension in 12 cases, abnormal pupil in 9 case and urinary retention in 7 case.Other symptoms included fatigue in 9 cases, emotional disorder in 4 cases, limb weakness in 2 cases, and sensory disturbance in 2 cases.All the patients were treated with intravenous immunoglobulin (IVIG), and 3 cases combined with glucocorticoid.Six patients with severe gastrointestinal symptoms were treated with intravenous nutrition; 4 patients were fed with jejunum, 3 cases of whom returned to normal diet within 1-12 months, and 1 patient was followed up for 5 years and 2 months.Hyponatremia was found in 7 cases, which recovered in 2-30 d. Nine cases were followed up for 1 month to 9 years.Seven cases were normal in daily work and study, with satisfactory nutritional status, stable mood and no relapse.Conclusions:The clinical manifestations of APD are varied.The initial symptoms are gastrointestinal motility disorders, orthostatic hypotension, urinary retention and hyponatremia.Individualized multi-disciplinary comprehensive management for symptoms, especially the comprehensive treatment of gastrointestinal motility disorders, management of postural hypotension, and the urinary system diagnosis and individualized treatment of can shorten the length of hospital stay and improve the prognosis effectively.

Myocardial infarction refers to severe coronary artery stenosis, which leads to continuous and complete occlusion of coronary artery and myocardial necrosis. Coronary artery stenosis (>50%) or occlusion can be seen in 90% of patients undergoing coronary angiography, but 10% of patients have no obvious stenosis, that is, non obstructive myocardial infarction (MINOCA). The incidence rate of MINOCA was about 6%, showing an upward trend year by year, with an average age of 55 years, of which 40% of women. Its etiology is complex, the onset is urgent, and the clinical manifestations are complex and changeable. The incidence of major adverse cardiovascular events (MACE) is very high, and the mortality rate within one year is as high as 3.5%. There is no unified diagnosis and treatment plan at present. In this paper, the etiology, diagnosis and treatment of MINOCA were reviewed.

To analyze the clinical presentation and the treatment process of one case of colchicine poisoning complicated with extra pontine myelinolysis and discuss its pathogenesis. Increasing the attention of hyponatremia caused by colchicine poisoning is of great significance for improving the prognosis and quality of life of patients.

To analyze the clinical presentation and the treatment process of one case of colchicine poisoning complicated with extra pontine myelinolysis and discuss its pathogenesis. Increasing the attention of hyponatremia caused by colchicine poisoning is of great significance for improving the prognosis and quality of life of patients.

Objective: To investigate the clinical significance of different samples (the peripheral blood, urine and skeletal muscle) that could be detected the large-scale single deletions directly by using next-generation sequencing in the diagnosis of Kearns-Sayre syndrome (KSS) by concluding the clinical and genetic features of KSS, in order to explore a non-invasive method for diagnosis. Methods: The clinical data, skeletal muscle′s pathology and enzymology and genetic results of individuals with KSS, who were hospitalized from October 2016 to October 2017 in Department of Neurology, Beijing Children′s Hospital, Capital Medical University, were collected.The gene tests were performed by using next generation sequencing technology and long-PCR technology of mitochondrial DNA(mtDNA) and the whole exon in the peripheral blood, urine and skeletal muscle. Results: Four patients were all consistent with the diagnosis criteria of KSS, among whom the age of onset was 8.2 years old on average, and the initial symptoms were statue, ptosis, headache and vomiting, and visual impairment.The common symptoms of the 4 cases were ophthalmoplegia, exercise intolerance, development delay, loss of appetite, hypotonia, muscle weakness, with cerebrospinal fluid protein concentration over 1 000 mg/L, the cerebral magnetic resonance imaging showed that abnormal signals in the brainstem, in addition, white matter, thalamus, basal ganglia, cerebrum and cerebellum atrophy could be found.Moreover, 3 cases had cardiac conduction block.Two cases had maternal family history.Molecular analysis of the 4 cases revealed the large-scale single deletions of mtDNA from the peripheral blood, the urine, the skeletal muscle through the next-generation sequencing, which were m. 6460-15590(9 131 bp del), m.8482-13446(4 964 bp del), m.6831-14981(8 151 bp del), m.7983-15495(7 513 bp del), respectively.Among 3 cases who did pedigree analysis, only the mother of case 4 was detected with the same variation of the proband. Conclusions KSS is a rare mitochondrial disease, which could be detected with the single large scale mtDNA deletions in the peripheral blood, urine and skeletal muscle.With the development of the methodology, the diagnosis of KSS maybe no longer than depends on the muscle biopsy with the next-generation sequencing.And the possibility to get the positive results in the peripheral blood and urine by the non-invasive method could improve the molecular diagnosis of KSS.