[Prognostic performance of pulmonary effective arterial elastance in patients with heart failure].

Objective: To explore the predictive value of pulmonary effective arterial elastance (Ea) in patients with heart failure (HF). Methods: This is a retrospective cohort study, which retrospectively included 284 patients with HF who underwent right heart catheterization at Heart Failure Center in Fuwai Hospital between September 2013 and February 2022. Data regarding baseline clinical characteristics, hemodynamic profiles, and prognosis were collected. Ea was calculated as mean pulmonary arterial pressure/stroke volume. Patients were divided into Ea<0.555 group and Ea≥0.555 group according to the median value of Ea (0.555 mmHg/ml, 1 mmHg=0.133 kPa). The primary outcome was the primary clinical event, set as the first occurrence of a series of composite events, including all-cause death, heart transplantation, left ventricular assist device implantation, and HF rehospitalization. Event-free survival was defined as the absence of primary clinical events. Spearman correlation analysis was used to calculate the correlation coefficient between Ea and parameters reflective of right heart function. The Kaplan-Meier analysis was used to compare the different groups for the estimation of outcomes with the log-rank test. We used Cox proportional-hazards regression models to estimate hazard ratios (HR) for primary clinical event. Subgroup analysis was performed based on the age, gender, New York Heart Association (NYHA) functional class, left ventricular ejection fraction, presence of pulmonary hypertension, and serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) values. We used receiver operating characteristic (ROC) curve to calculate the area under the curve (AUC) of Ea for predicting event-free survival in patients with HF. Results: The median age was 51 years, and 206 (72.5%) patients were male. Ea and pulmonary vascular resistance (PVR) were significantly correlated (r=0.698, P<0.001). The correlation between Ea and pulmonary arterial elastance (PAC) were even more significant (r=-0.888, P<0.001). Compared with Ea<0.555 group, Ea≥0.555 group presented with higher serum NT-proBNP values (4 443 (1 792, 8 554) ng/L vs. 1 721 (480, 4 528)ng/L,P<0.001), higher PVR (3.4 (2.5, 4.7) Wood vs. 1.4 (0.9, 2.2) Wood, P<0.001), lower cardiac output (3.0 (2.3, 3.9) L/min vs. 4.3 (3.8, 4.9) L/min, P<0.001), and lower PAC (1.6 (1.3, 2.0) ml/mmHg vs. 4.0 (3.0, 6.0) ml/mmHg, P<0.001). The median follow-up time was 392 (166, 811) days. The Kaplan-Meier survival curve demonstrated a lower event-free survival rate in the Ea≥0.555 group compared to the Ea<0.555 group (Plog-rank<0.001). After multivariate adjustment, Ea (HR=1.734, P<0.001) remained significantly associated with the primary outcome. Subgroup analysis indicated that Ea was associated with the primary outcome across all subgroups. The AUC was 0.724 (P<0.001) for Ea to predict event-free survival calculated from ROC analysis. Conclusions: Ea is closely related to parameters reflective of right ventricular afterload. Increased Ea is an independent predictor of adverse outcomes in patients with HF.

[Clinical characteristics of patients referred to cardio-oncology clinic].

To explore characteristics of outpatients in a single cardio-oncology clinic, patients visiting cardio-oncology clinic of Fuwai Hospital CAMS&PUMC (Beijing, China) from January 2020 to December 2021 were analyzed retrospectively. In total, 330 patients were included, the median age (Q1, Q3) was 58(46, 66) years, and there were 192 females (58.2%). The purposes for visit included an evaluation and treatment of cardiovascular adverse reactions (n=247, 74.8%), pre-antitumor therapy assessment (n=51, 15.5%), and management of primary or metastatic cardiac tumors (n=32, 9.7%). For patients with cardiovascular adverse reactions, the most common tumor type was breast cancer (n=88, 29.5%), followed by gastrointestinal cancer (n=70, 23.5%), and hematological cancers (n=62, 20.8%). Among them, 236 cases (95.5%) had received antitumor drugs in the past; 38 cases (15.4%) had a history of chest radiotherapy; some cases were complicated with hypertension (n=69, 23.2%) and/or hyperlipidemia (n=69, 23.2%); 42 cases (14.1%) had a history of coronary heart disease; and 16 cases (5.4%) were complicated with atrial fibrillation or flutter. Among 32 patients with cardiac tumors, 11 cases (34.4%) had primary malignant tumors; 6 cases (18.8%) had benign tumors; 2 cases (6.3%) had metastatic tumors; and 13 (40.6%) had unknown pathological types. This study explores the epidemiology of cardio-oncology in China and provides clinical insights for the future development of cardio-oncology. In the future, it is still necessary to study the benefits of cardio-oncology clinics and develop standardized indicators to evaluate their benefits.

[Research advances in the pathogenesis of exfoliative glaucoma].

Exfoliative glaucoma is a type of glaucoma secondary to pseudoexfoliation syndrome. In recent years, great progress has been made in the research of pathogenesis and risk factors of exfoliative glaucoma. A variety of risk genes, abnormal growth factors and cytokines, changes in the anterior and posterior segments have been found. Based on the systematic summary of these achievements, this article points out the problems that need to be further studied, so as to provide a reference for future research in this field.

[Study on syndromic deafness caused by novel pattern of compound heterozygous variants in the CDH23 gene].

Objective: To explore the pathogenic variants of a family with syndromic deafness by high-throughput sequencing. Methods: The family was from Puyang City, Henan Province, and had four members, including two with syndromic deafness. The proband and his sister had congenital deafness, and their parents had normal phenotypes. The clinical phenotype of the family was characterized using clinical examinations and pedigree analysis. The clinical examinations included imaging examination, audiometry (pure tone audiometry, acoustic immittance, brainstem auditory evoked potential, and otoacoustic emission), vestibular function test, and ophthalmic examination (visual acuity test, visual field test, fundus examination, visual evoked potential, and electroretinogram). Target exome sequencing of 129 known deafness genes and bioinformatics analysis were used to screen suspected pathogenic variants. Sanger sequencing and minigene assay were used to verify and functionally investigate the mutation detected, respectively. According to the standards and guidelines for interpreting genetic variants proposed by the American College of Medical Genetics and Genomics, the variants c.6049G>A and c.8699A>G were classified as pathogenic/likely pathogenic, and the variant c.9856C>G was classified as variants of uncertain significance. Results: The probands and his sister had severe sensorineural hearing loss with decreased binocular vision, night blindness, decreased peripheral visual field sensitivity and partial visual field defect, and normal vestibular function. Both of them had three CDH23 mutations, including CDH23 (NM_022124.5) c.6049G>A (p.Gly2017Ser),c.9856C>G (p.His3286Asp), and c.8699A>G (p. Asp2900Gly), The first two were inherited from the father, and the last one was from the mother. The missense variants c.9856C>G and c.8699A>G were not included in the gnomad database. The missense mutation c.6049G>A was located in the last position of exon 46 and was predicted to affect splicing by bioinformatics software. The minigene experiment showed that the mutation cause exon skipping of exon 46, resulting in an abnormal protein. Conclusions: Compound heterozygous variations of the CDH23 are the leading cause of USH1D in the family. This study confirms that the compound heterozygosity of splicing and missense variants of the CDH23 gene could lead to USH1D.

Cross-resistance and combined cytotoxic effects of paclitaxel and cisplatin in bladder cancer cells.

PURPOSE: We studied the cross-resistance and combined cytotoxic effects of cisplatin and paclitaxel in bladder cancer cells in vitro. MATERIALS AND METHODS: The cytotoxicity of the 2 agents alone or in combination were studied in the bladder cancer cell line NTUB1 and the 2 sublines NTUB1/P, which is cisplatin resistant, and NTUB1/T, which is paclitaxel resistant, using the microculture tetrazolium assay. Schedule dependence of the 2-drug combination was assayed using 3 treatment schedules, including 1 concurrent and 2 sequential exposures. RESULTS: The mean cisplatin concentration plus or minus standard error of the means inhibiting 50% of the growth of NTUB1, NTUB1/P and NTUB1/T was 1.9 +/- 0.19, 19.3 +/- 2.33 and 2.1 +/- 0.15 microM., respectively, and the mean paclitaxel concentration inhibiting 50% of the growth of the 3 cell lines was 30 +/- 3.9, 1,033 +/- 120 and 110 +/- 15 nM., respectively. NTUB1/P had strong cross-resistance to paclitaxel. In contrast, NTUB1/T was as sensitive as NTUB1 to cisplatin. On median effect analysis the combined effects of the 2 agents given concurrently were sub-additive in the low fraction affected range of 0.1 to 0.3 and additive in the median to high fraction affected range of 0.4 to 1.0 in the 3 cell lines. Combined cytotoxicity was more synergistic when paclitaxel was given 24 hours earlier than cisplatin. The effects were less synergistic when cisplatin was given before paclitaxel. This phenomenon was noted in sensitive and resistant cells. CONCLUSIONS: In our bladder cancer cell model cisplatin resistant cells have strong cross-resistance to paclitaxel, whereas paclitaxel resistant cells are sensitive to cisplatin. The combined effects may be optimized by sequential use of the 2 agents, preferably paclitaxel given 24 hours before cisplatin. Our results have clinical implications for the treatment of bladder cancer.

Characterization of chemoresistance mechanisms in a series of cisplatin-resistant transitional carcinoma cell lines.

We explored the mechanisms of cisplatin resistance in a series of bladder transitional carcinoma cells that are either sensitive or progressively resistant to cisplatin. Resistant lines were raised by chronic exposure of the parental cells to progressively increased concentrations of cisplatin. The cisplatin IC50s of the sensitive and the three resistant cells were 4.3, 25.0, 40.4, and 52.2 microM, respectively. The expressions of glutathione S-transferase pi (GST-pi) and multidrug resistance-associated protein (MRP) were enhanced in a dose-response manner as cells acquired progressive cisplatin resistance. Expression of mdr-1 transcript was detected in the three resistant lines but not in the sensitive line. Glutathione contents were increased in resistant cells, yet the trend of increase did not reach statistical significance (p = 0.061). In conclusion, transitional carcinoma cells may gain cisplatin resistance through multiple pathways including up-regulation of GST-pi, MRP and possibly mdr-1. Glutathione contents may play a less significant role in cisplatin chemoresistance.

Megestrol acetate antagonizes cisplatin cytotoxicity.

Megestrol acetate (MGA) is being widely used for the improvement of appetite and performance status in patients receiving chemotherapy, especially cisplatin-containing therapy. However, little is known about whether MGA has an effect on cisplatin cytotoxicity. We have investigated this using two transitional carcinoma cell lines, i.e. the cisplatin-sensitive parental line NTUB1 and the resistant daughter line NTUB1/P. Combined effects of MGA and cisplatin were assayed with a microculture chemosensitivity method. We explored the level changes of several cisplatin detoxification mechanisms, including metallothionein (MT), glutathione S-transferase-pi (GST-pi) and glutathione (GSH) levels in cells treated with or without MGA. After treatment with 10 microns MGA for 24 h, the cisplatin IC50s of NTUB1 and NTUB1/P increased 1.4- (p = 0.03) and 1.6- (p = 0.02) fold, respectively. By median effect analysis, the combinations of MGA and cisplatin in the two cells appeared to produce an antagonistic interaction. By Northern analysis, MT transcript levels in both cells were significantly upregulated after treatment with MGA, as compared to those without treatment. Exposure to MGA in either sensitive or resistant cells did not alter GST-pi levels as shown by immunoblotting analysis. Cellular GSH content was increased only in NTUB1/P (p = 0.0036) but remained unchanged in NTUB1 cells (p = 0.29) after MGA exposure. In conclusion, MGA may antagonize cisplatin cytotoxicity by upregulating cellular MT and GSH levels. Use of MGA in cisplatin-containing chemotherapy may impair tumor response by antagonizing cisplatin antitumor activity.

Difference in effects of classic and phospholipid hydroperoxide glutathione peroxidases on liver lipid peroxide level in selenium-deficient rats.

When weanling male rats of the Wistar strain were fed a selenium-deficient diet, the activity of classic glutathione peroxidase (GPx) in liver cytosol decreased rapidly. In contrast, the activity of phospholipid hydroperoxide GPx (PHGPx) in the cytosol decreased only slowly. Despite the marked decrease in classic GPx activity, the lipid peroxide level in the liver did not change until 6 weeks after the start of the feeding, whereas the level was significantly increased by 9 weeks, by which time PHGPx activity and its protein level had markedly diminished. These data indicate that PHGPx is much more crucial than classic GPx in preventing the elevation of liver lipid peroxide level in selenium-deficient rats.

Presenile (early ageing) changes in tissues of Kaschin-Beck disease and its pathogenetic significance.

The selenium level and activity of glutathione peroxidase in blood of children living in Kaschin-Beck disease (KBD) endemic areas were lower than that in nonendemic areas. KBD children were deficient in selenium, their lipid components, structure and function of the red cell membrane and cartilage tissue were abnormal. That is, the phospholipid (PL) content in the tissues of the patient was less than that of the controls in endemic and non-endemic areas. Especially as the phosphatidylcholine (PC) content decreased significantly, but sphingomyelin (SM) increased, the molar ratio of SM/PC and cholesterol (Ch)/PL increased. Increase of acanthocyte content was seen under the electron microscope and the fragility of erythrocytes was also increased. It indicated that there were membrane defects and membrane damage in KBD. At the same time, the sulfation extent of mucopolysaccharides in cartilage of patients was lower, and the collagen content was higher than that of controls. The presenile changes in lipid composition, structure and function of biomembranes and cartilage metabolism of KBD are very significant in studies on the aetiological pathogenesis of KBD and other ageing diseases.