0.05 ). Conclusions With low initial FGF addition of N2O does not affect the uptake of desflurane. The low-flow desflurane anesthesia is safe and economical.

Glucocorticoids ; therapeutic use ; Humans ; Muscular Dystrophy, Duchenne ; drug therapy

Objective To discuss the clinical features and treatment of isovaleric academia (IVA) patients,and to gain more comprehensive understanding of isovaleryl-CoA dehydrogenase(IVD) mutation in 2 siblings in order to raise awareness to prevent the occurrence of IVA.Methods The clinical history and laboratory test of 2 cases of children with IVA were carried out.The exons and neighboring introns of IVD gene of the whole family were PCR-amplified for DNA sequencing.The literature review of IVA in China was also conducted.Results Organic acid analysis of urine by GC/MS for both siblings showed extremely elevated concentrations of isovaleric glycine.For the older sibling,an acute episode of IVA caused severe metabolic stress and eventually death in the neonatal period.However,the disease was well-controlled for the younger sibling due to timely treatment and follow-up care for 2 years.The DNA sequencing of the IVD gene in the family revealed a novel c.1016G ＞ A(C339Y) heterozygous mutation in mother and both of the siblings.No IVD mutation was detected in father or in any of the 50 cases of healthy controls.According to literature review,15 cases of IVA were reported in recent 15 years in China,including neonatal onset (11 cases),acute episode (12 cases),odor of sweaty feet (12 cases),pancytopenia (9 cases),hyperammonemia (5 cases),hypocalcemia (6 cases),and 6 cases of death were reported.Additionally,5 cases that received treatment of BCAA-free formula milk showed positive outcome.However,only 2 cases were followed up for more than 2 years.Conclusions Two new IVA patients carrying c.1016G ＞ A(C339Y) mutation were reported in China.The mutation may lead to conformational change and functional deficient of the IVD protein.It is also necessary to point out that using direct DNA sequencing can not identify all patients with IVA due to limitations of this technology,and thus clinicians should be aware of the possibility of genetic misdiagnosis.Moreover,there is a trend of increasing IVA in China in recent years.

Objective To investigate the effects of desflurane on the delayed rectifier potassium current (Ik ) in acutely dissociated rat parietal cortical neurons. Methods Wistar rats between 10- and 14-day old of both sexes were used. The parietal cortical neurons were acutely dissociated enzymatically. The extracellular fluid saturated with 0.3,0.6 and 0.9 mmol/L desflurane was added to the culture dish, then the effects of different concentrations of desflurane on Ik were investigated by using the whole-cell patch-clamp technique in acutely dissociated rat parietal cortical neurons. Results IK was inhibited by desflurane in a concentration-dependent manner ( P ＜0.01). The V1/2 of the activation and inactivation curves and the slop factor had no change after giving 0.6 mmol/L desflurane (P ＞ 0.05). Conclusion Desflurane inhibits delayed rectifier potassium channels of parietal cortical neurons of rats in a concentration-dependent manner, and has no effect on the activation and inactivation of delayed rectifier potassium channels, indicating that the change in the excitability of the channel is not involved in the mechanism of inhibitory effect of desflurane, and the other reasons may be involved in the mechanism.

Cognitive dysfunction,as a common symptom among patients with chronic fatigue syndrome (CFS) and patients with fibromyalgia(FM),impacts on life quality,occupation and study of these patients.However,the neural correlates to the cognitive impairment are unknown.Event related potentials,which reflect the information processing objectively and constantly,provide possibility for taking a insight into and estimating the dysfunction.By summarizing and analyzing studies in event related potentials about chronic fatigue syndrome,fibromyalgia,we found that CFS patients were characterized with prolonged latency of N200 and P300 accompanied by decreased P300 amplitude when they performed on Oddball paradigm,fibromyalgia patients were characterized with lower P300 amplitude when they concentrated on Oddball task,meanwhile,fibromyalgia patients also showed decreased P100/N100,P200,P300,LPC in emotional word decision task and somatic pictures decision task.It's suggests that the cognitive dysfunction in CFS is mainly caused by slowed speed of information identification and classification,whereas in FM it's dysregulation in attention control system results in the cognitive dysfunction.Limitations in current studies and prospects on researches about cognitive dysfunction in CFS for future were also discussed.

Objective:To analyze the pathogenic gene and prenatal diagnosis of a family with intellectual disability.Methods:Out of this family consisting of 17 members in three generations, four males had intellectual disability. The proband's elder sister (Ⅱ-7) visited Henan Provincial People's Hospital in Oct 2019 for genetic counseling at 8 weeks of gestation. After informed consent was obtained, peripheral blood samples of the family members were collected. The whole exome sequencing was performed on the genome DNA of the proband (Ⅱ-9, male) and his parents to screen the candidate variants for phenotype co-segregated analysis by Sanger sequencing. The expression vectors were constructed by homologous recombination and the splicing experiments were performed in vitro. Reverse transcription polymerase chain reaction, Sanger sequencing, and TA clone sequencing were used to analyze the effect of candidate variants on splicing. After the pathogenic variant was determined the proband's elder sister underwent prenatal diagnosis (Ⅲ-7) using goldeneyeTM20A genotyping system and Sanger sequencing. Results:A hemizygous synonymous variant of c.1302G>A (p. S434S) in DLG3 gene was found in the proband by whole exome sequencing, which was carried by his mother (Ⅰ-1) and co-segregated with the phenotype in other family patients. In vitro splicing experiment showed that c.1302G>A variant led to abnormal splicing of 88.24% transcripts, which further resulted in the reading frame shift and protein function impairment. The mutation was not detected in the fetus (Ⅲ-7), who was born alive later and showed no abnormal mental or behavioral development at the age of one and a half year and is still being followed up. Conclusions:The synonymous mutation c.1302G>A in DLG3 gene was the etiopathogenesis of X-linked intellectual disability in this family.

Lipids have been found to modulate tumor biology, including proliferation, survival, and metastasis. With the new understanding of tumor immune escape that has developed in recent years, the influence of lipids on the cancer-immunity cycle has also been gradually discovered. First, regarding antigen presentation, cholesterol prevents tumor antigens from being identified by antigen presenting cells. Fatty acids reduce the expression of major histocompatibility complex class I and costimulatory factors in dendritic cells, impairing antigen presentation to T cells. Prostaglandin E2 (PGE2) reduce the accumulation of tumor-infiltrating dendritic cells. Regarding T-cell priming and activation, cholesterol destroys the structure of the T-cell receptor and reduces immunodetection. In contrast, cholesterol also promotes T-cell receptor clustering and relative signal transduction. PGE2 represses T-cell proliferation. Finally, regarding T-cell killing of cancer cells, PGE2 and cholesterol weaken granule-dependent cytotoxicity. Moreover, fatty acids, cholesterol, and PGE2 can improve the activity of immunosuppressive cells, increase the expression of immune checkpoints and promote the secretion of immunosuppressive cytokines. Given the regulatory role of lipids in the cancer-immunity cycle, drugs that modulate fatty acids, cholesterol and PGE2 have been envisioned as effective way in restoring antitumor immunity and synergizing with immunotherapy. These strategies have been studied in both preclinical and clinical studies.

Mevalonate metabolism plays an important role in regulating tumor growth and progression; however, its role in immune evasion and immune checkpoint modulation remains unclear. Here, we found that non-small cell lung cancer (NSCLC) patients with higher plasma mevalonate response better to anti-PD-(L)1 therapy, as indicated by prolonged progression-free survival and overall survival. Plasma mevalonate levels were positively correlated with programmed death ligand-1 (PD-L1) expression in tumor tissues. In NSCLC cell lines and patient-derived cells, supplementation of mevalonate significantly up-regulated the expression of PD-L1, whereas deprivation of mevalonate reduced PD-L1 expression. Mevalonate increased CD274 mRNA level but did not affect CD274 transcription. Further, we confirmed that mevalonate improved CD274 mRNA stability. Mevalonate promoted the affinity of the AU-rich element-binding protein HuR to the 3'-UTR regions of CD274 mRNA and thereby stabilized CD274 mRNA. By in vivo study, we further confirmed that mevalonate addition enhanced the anti-tumor effect of anti-PD-L1, increased the infiltration of CD8⁺ T cells, and improved cytotoxic function of T cells. Collectively, our findings discovered plasma mevalonate levels positively correlated with the therapeutic efficacy of anti-PD-(L)1 antibody, and provided the evidence that mevalonate supplementation could be an immunosensitizer in NSCLC.

Immunotherapy strategies targeting the programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) pathway in clinical treatments have achieved remarkable success in treating multiple types of cancer. However, owing to the heterogeneity of tumors and individual immune systems, PD-L1/PD-1 blockade still shows slow response rates in controlling malignancies in many patients. Accumulating evidence has shown that an effective response to anti-PD-L1/anti-PD-1 therapy requires establishing an integrated immune cycle. Damage in any step of the immune cycle is one of the most important causes of immunotherapy failure. Impairments in the immune cycle can be restored by epigenetic modification, including reprogramming the environment of tumor-associated immunity, eliciting an immune response by increasing the presentation of tumor antigens, and by regulating T cell trafficking and reactivation. Thus, a rational combination of PD-L1/PD-1 blockade and epigenetic agents may offer great potential to retrain the immune system and to improve clinical outcomes of checkpoint blockade therapy.

[This corrects the article DOI: 10.1016/j.apsb.2023.04.002.].