BACKGROUND: Recent studies have shown that sodium-glucose cotransporters-2 (SGLT2) inhibitors significantly improve major adverse cardiovascular events in heart failure with preserved ejection fraction (HFpEF) patients, but the exact mechanism is unknown. Ferritinophagy is a special form of selective autophagy that participates in ferroptosis. In this study, we aimed to investigate whether ferritinophagy was activated during the occurrence of HFpEF, and whether canagliflozin (CANA) could inhibite ferritinophagy. METHODS: We reared Dahl salt-sensitive (DSS) rats on a high-salt diet to construct a hypertensive HFpEF model, and simultaneously administered CANA intervention. Then we detected indicators related to ferritinophagy. RESULTS: The expression of nuclear receptor coactivator 4 (NCOA4), as well as microtubule-associated proteins light chain 3 (LC3), Bcl-2 interacting protein 1 (Beclin-1) and p62, were upregulated in HFpEF rats, accompanied by the downregulation of ferritin heavy chain 1 (FTH1), upregulation of mitochondrial iron transporter sideroflexin1 (SFXN1) and increased reactive oxygen species (ROS) production. Above changes were diminished by CANA. CONCLUSION Ferritinophagy is activated in HFpEF rats and then inhibited by CANA, leading to HFpEF benefits. The inhibition of ferritinophagy could provide new prospective targets for the prevention and treatment of HFpEF, and provide new ideas for investigating the mechanism of cardiovascular benefit of SGLT2 inhibitors.

Objective:The clinical significance of aural fullness in patients with vestibular migraine（VM） remains unclear, and it is yet to be determined whether VM with aural fullness represents a distinct subtype of VM; this study aimed to compare differences in demographic characteristics, clinical manifestations, audiological findings, and vestibular function tests between VM patients with and without aural fullness, and explore whether the former is a subtype of VM and whether it requires differentiated treatment. Methods:A total of 174 VM patients were enrolled, including 75 with aural fullness（aural fullness group） and 99 without aural fullness（non-aural fullness group）; demographic data, vertigo characteristics, medical history, family history, pure-tone audiometry, and vestibular function tests were thoroughly recorded, and independent samples t-test and chi-square test were used for inter-group comparisons. Results:①Regarding demographic characteristics, the age of the aural fullness group was significantly lower than that of the non-aural fullness group[（44.08±13.97） years vs. （49.45±16.05） years, P=0.020）, while the two groups showed consistent gender distribution（more females than males） with no statistically significant difference. ②For aural fullness characteristics, unilateral aural fullness accounted for 65.0% in the aural fullness group, significantly higher than bilateral aural fullness（35.0%, P<0.001）. ③In terms of vertigo characteristics, there were no statistically significant inter-group differences in the nature of attacks（rotational vertigo: 36.0% vs. 41.4%, P=0.463; dizziness: 21.3% vs. 11.1%, P=0.064; rotational vertigo or dizziness: 29.3% vs. 25.3%, P=0.548; dizziness with unsteady gait: 9.3% vs. 11.1%, Fisher P=0.806; visual oscillation with unsteady gait: 4.0% vs. 11.1%, Fisher P=0.086）, duration（several hours: 34.7% vs. 33.3%, P=0.841; several minutes: 22.7% vs. 21.2%, P=0.808; several seconds: 5.3% vs. 8.1%, Fisher P=0.557; several days: 9.3% vs. 9.1%, Fisher P=1.000; multiple combined patterns: 17.3% vs. 15.2%, P=0.686）, or incidence of nausea and vomiting（84.0% vs. 72.7%, P=0.071, no statistical significance）. ④No statistically significant inter-group differences were found in medical history and family history, including motion sickness history（8.0% vs. 4.0%, Fisher P=0.337）, headache history（22.7% vs. 34.3%, P=0.084）, and family history of dizziness（12.0% vs. 14.1%, P=0.666）. ⑤For audiological characteristics, 21.3%（16/75） of patients in the aural fullness group had low-frequency hearing loss, significantly higher than 5.1% in the non-aural fullness group（χ²=10.66, P=0.001）; among patients with unilateral aural fullness, 28.6%（14/49） had ipsilateral low-frequency hearing loss, significantly higher than 7.7%（2/26） of those with bilateral aural fullness（χ²=4.41, P=0.036）; however, there was no statistically significant difference in the rate of bilateral high-frequency hearing loss between the two groups（54.7%[41/75]vs. 50.5%[50/99], χ²=0.30, P=0.586）. ⑥In vestibular function tests, no statistically significant inter-group differences were observed in smooth pursuit type Ⅲ/Ⅳ（12.5% vs. 13.1%, P=0.913）, caloric test with CP>25%（31.2% vs. 37.4%, P=0.411）, abnormal video head impulse test（vHIT） rate（30.8% vs. 32.6%, P=0.865）, or abnormal vestibular evoked myogenic potential（VEMP） rate（53.8% vs. 38.9%, Fisher P=0.484）. Conclusion:VM patients with aural fullness have an earlier age of onset, with nearly 1/4 accompanied by low-frequency hearing loss; VM patients with and without aural fullness are highly consistent in gender distribution, nature/duration of vertigo, vestibular function impairment, and presence of bilateral high-frequency hearing loss, suggesting that the core clinical phenotypes of the two groups are consistent, while the former has an earlier age of onset and a higher proportion of unilateral hearing loss, which may be related to the pathological mechanism of VM and inner ear microcirculation disorders.
Humans ; Female ; Male ; Middle Aged ; Adult ; Migraine Disorders/classification* ; Young Adult ; Vertigo ; Age of Onset ; Aged ; Hearing Loss

The efficient production of L-glutamate is dependent on the product's rapid efflux, hence researchers have recently concentrated on artificially modifying its transport system and cell membrane wall structure. Considering the unique composition and structure of the cell wall of Corynebacterium glutamicum, we investigated the effects of CmpLs on L-glutamate synthesis and transport in SCgGC7, a constitutive L-glutamate efflux strain. First, the knockout strains of CmpLs were constructed, and it was confirmed that the deletion of CmpL1 and CmpL4 significantly improved the performance of L-glutamate producers. Next, temperature-sensitive L-glutamate fermentation with the CmpL1 and CmpL4 knockout strains were carried out in 5 L bioreactors, where the knockout strains showcased temperature-sensitive characteristics and enhanced capacities for L-glutamate production under high temperatures. Notably, the CmpL1 knockout strain outperformed the control strain in terms of L-glutamate production, showing production and yield increases of 69.2% and 55.3%, respectively. Finally, the intracellular and extracellular metabolites collected at the end of the fermentation process were analyzed. The modification of CmpLs greatly improved the L-glutamate excretion and metabolic flux for both L-glutamate production and transport. Additionally, the CmpL1 knockout strain showed decreased accumulation of downstream metabolites of L-glutamate and intermediate metabolites of tricarboxylic acid (TCA) cycle, which were consistent with its high L-glutamate biosynthesis capacity. In addition to offering an ideal target for improving the stability and performance of the industrial strains for L-glutamate production, the functional complementarity and redundancy of CmpLs provide a novel target and method for improving the transport of other metabolites by modification of the cell membrane and cell wall structures in C. glutamicum.
Corynebacterium glutamicum/genetics* ; Glutamic Acid/biosynthesis* ; Fermentation ; Metabolic Engineering ; Bacterial Proteins/metabolism* ; Bioreactors/microbiology* ; Gene Knockout Techniques

Objective To evaluate the bioequivalence of the test preparation and reference preparation of azithromycin capsules in healthy Chinese subjects.Methods A total of 48 subjects were enrolled in this study using a randomized,open,two-sequence,cross design.Each subject received a single oral dose of azithromycin capsules test drug(T)or reference drug(R)for 250 mg.The concentrations of azithromycin in plasma were determined by Liquid Chromatograph Mass Spectrometer,and the pharmacokinetic parameters were calculated by WinNonlin 8.1 software to evaluate the bioequivalence.Results The main pharmacokinetic parameters of azithromycin after a single fasting dose of the test drug and the reference drug were as follows:the Cmax were respectively(319.89±127.35)and(330.41±122.11)ng·mL-1;AUC0-192h were respectively(2 423.04±587.15)and(2 489.97±685.73)ng·h·mL-1;AUC0-∞ were respectively(2 753.40±644.96)and(2 851.71±784.05)ng·h·mL-;tmax were respectively(2.60±1.11)and(2.62±1.13)h;t1/2 were respectively(76.76±15.14)and(79.83±17.14)h.The 90％confidence intervals for the geometric mean ratios of Cmax,AUC0-192h and AUC0-∞ of T and R were 87.52％-107.18％,91.46％-105.80％and 91.17％-105.06％,respectively.Conclusion The test preparation of azithromycin capsule was bioequivalent to the reference preparation under fasting condition.

Relative to hepatitis B virus(HBV)monoinfection,HBV/hepatitis D virus(HDV)co-infection may be associated with more severe liver disease,leading to increased rates of cirrhosis,hepatocellular carcinoma,hepatic decompensation,and liver failure.The treatment of chronic HDV infection is essential and urgent.No drugs with established Efficacy and safety data have been approved for the treatment of chronic HDV infection.There are several new drugs are in clinical development stage now.We review the mechanism of action,research and development progress,and clinical trial design of new drugs currently in the clinical development stage,as well as the recommendations of regulatory agencies and academia for the clinical trial design of new drugs for the treatment of chronic HDV infection.And discuss the key points of confirmatory clinical trial design.

Objective To explore the efficacy of pancreatic kallidinogenase enteric-coated tablet combined with irbesartan tablet in the treatment of elderly patients with type 2 diabetic nephropathy(DN).Methods Elderly patients with type 2 DN were selected as the research subjects,and were randomized into control group and treatment group.The control group was given 150 mg of irbesartan tablets once a day,while the treatment group was given 240 U of pancreatic kallidinogenase enteric-coated tablets three times a day on the basis of the control group.The clinical efficacy,renal function indicators[serum creatinine(SCr),blood urea nitrogen(BUN),urinary albumin excretion rate(UAER)],hemodynamic indicators[fibrinogen(FIB),whole blood viscosity,hematocrit(HCT)],microvascular lesion indicators[vascular endothelial growth factor(VEGF),soluble intercellular adhesion molecule-1(sICAM-1)],B-ultrasound detection indicators[maximum aortic flow velocity(Vmax),minimum diastolic flow velocity(Vmin),resistance index(RI)at the renal hilum]before and after treatment and adverse drug reactions were compared between both groups.Results After treatment,the total effective rates in control group and treatment group were 85.42％and 97.92;SCr levels were(90.47±18.14)and(80.28±12.04)μmol·L-1;BUN levels were(7.24±1.34)and(6.54±1.21)mmol·L-1;UAER levels were(36.17±6.07)and(31.04±5.21)μg·min-1;FIB levels were(4.32±0.59)and(3.95±0.48)g·L-1;whole blood viscosity values were(7.38±1.15)and(6.81±0.98)mPa·s;HCT levels were(38.63±7.01)％and(36.17±6.48)％;VEGF levels were(254.18±45.59)and(212.14±40.48)pg·mL-1;human sICAM-1 levels were(336.40±61.57)and(295.30±58.46)pg·L-1;the Vmax of renal artery were(72.58±3.60)and(74.98±3.78)cm·s-1;the Vmin values were(22.48±3.14)and(24.83±3.63)cm·s-1;the RI values were 0.73±0.06 and 0.68±0.07,respectively.There were statistical differences in the above indicators between control group and treatment group(all P＜0.05).The total incidence eares of adverse drug reactions in control group and treatment group were 4.17％(2 cases/48 cases)and 8.33％(4 cases/48 cases)respectively(P＞0.05).Conclusion Pancreatic kallidinogenase enteric-coated tablet combined with irbesartan tablet can effectively improve the renal function of elderly patients with type 2 DN,improve the blood flow and delay microvascular lesion,and enhance the efficacy,therefore it is safe and effective.

Objective:To monitor the liver oxygen saturation (rStO 2-liv) and the intestinal oxygen saturation (rStO 2-abd) in very low birth weight infants (VLBW) using near infrared spectroscopy (NIRS) and explore the difference between the two indicators and their clinical significance. Methods:This prospective study included newborns with a birth weight of less than 1 500 g at the Nanjing Women and Children′s Healthcare Hospital, from October 1, 2022 to March 31, 2023.On the 7 th day after birth, Gutcheck NEC scores were evaluated, followed by continuous NIRS measurement for 8 hours.Clinical data and NIRS measurements were collected and comparatively analyzed.The differences between groups were compared by two independent samples t-test and One-Way ANOVA. The diagnostic value of NIRS was analyzed using receiver operating haracteristic curves. Results:A total of 42 VLBW infants were enrolled in this study.There was no statistically significant difference between rStO 2-liv and rStO 2-abd ( P=0.117).According to the Gutcheck NEC score, there were 7 patients in the low-risk group, 29 in the medium-risk group, and 6 in the high-risk group.No statistically significant difference was observed in rStO 2-liv among the different risk groups ( F=2.145, P=0.131).The rStO 2-abd decreased significantly with increasing risk ( F=5.127, P=0.011).The Bland-Altman plot indicated no consistency between rStO 2-liv and rStO 2-abd ( P=0.024).The receiver operator characteristic curve showed that the area under the curve (AUC) for rStO 2-abd diagnosing the high-risk Gutcheck NEC score was 0.800, with a cutoff value of 41.41%, sensitivity of 85.70%, and specificity of 48.60%. Conclusions:Simultaneous measurement of rStO 2-liv and rStO 2-abd using NIRS is safe and feasible in VLBW infants, but the two measures can not be substituted for each other.Low rStO 2-abd (<41.41%) indicates a higher risk of necrotizing enterocolitis in infants.

Objective: To explore the relationship between parenting style and emotional behavior problems in children with development dyslexia (DD), so as to provide reference for family support and intervention measures. Methods: From June to September 2023, 201 children in DD group and typically developing matched by age and sex were selected from the students in grades 3-6 of 4 primary schools in a district of Xinjiang by random cluster sampling method. The Childrens Version of the Parenting Style Scale and the Strength and Difficulty Scale were administered, and the occurrence of childrens emotional behavior problems and parentingstyles in the two groups were compared by Chisquare test and Wicoxon rank sum test. The correlation between parents parenting styles and childrens emotional behavior problems was analyzed by generalized linear regression. Results: The detection rates of emotional behavior problems were 45.77% in DD group and 15.42% in normal control children group. The differences in parenting styles between fathers and mothers of the DD group and the normal control group were statistically significant in terms of emotional warmth, parenting anxiety, and overprotection (Z=4.02, 29.03; 4.94, 26.32; 23.47, 5.30, P<0.05). Generalized linear regression analysis showed that father affective warmth was positively correlated with emotional symptoms, hyperactivity, peer interaction problems and prosocial behaviors (β=0.08, 0.05, 0.05, 0.09, P<0.05). The emotional warmth of mothers in DD group was negatively correlated with emotional symptoms, conduct problems, hyperactivity and peer interaction problems (β=-0.18, -0.08, -0.07, -0.08, P<0.05). Conclusions Parenting style is an important factor affecting the emotional behavior problems of DD children. Improving parenting style can reduce the occurrence of emotional behavior problems of DD children.

With the optimization of surgical technologies and postoperative management regimens, the number of lung transplantation has been significantly increased, which has become an important treatment for patients with end-stage lung disease. However, due to the impact of comprehensive factors, such as bronchial ischemia and immunosuppression, the incidence of airway stenosis after lung transplantation is relatively high, which severely affects postoperative survival and quality of life of lung transplant recipients. In recent years, with the improvement of perioperative management, organ preservation and surgical technologies, the incidence of airway stenosis after lung transplantation has been declined, but it remains at a high level. Early diagnosis and timely intervention play a significant role in enhancing clinical prognosis of patients with airway stenosis. In this article, the general conditions, diagnosis, treatment and prevention of airway stenosis after lung transplantation were reviewed, aiming to provide reference for comprehensive management of airway stenosis after lung transplantation and improving clinical prognosis of lung transplant recipients.