Objectives:To analyze the consistency of evaluating left ventricular hemodynamics (HDF) based on single plane and multi plane cine sequences of magnetic resonance mitral valve orifice.Methods:A prospective study was conducted on 48 healthy adults, and two methods were used to measure the mitral valve diameter and calculate HDF parameters. The first method was to measure the diameter of the mitral valve opening in the left ventricular three chamber cine sequence; The second method is to measure the mitral valve diameter using cine sequences of two chamber, three chamber, and four chamber hearts, and then take the average value. Paired t-tests were used to compare the differences in HDF measured by two methods, and Pearson correlation coefficient ( r), intra group correlation coefficient ( ICC), and Bland-Altman analysis were used to test the consistency and reproducibility of the two methods. Results:The root mean square (RMS) of longitudinal HDF calculated using single plane and multi plane mitral valve diameters were [(17.28±4.41)% vs (17.21±4.61)%] ( P=0.379) for the entire cardiac cycle, [(21.45±5.54)% vs (21.49±5.68)%] ( P=0.646) for systolic phase, and [(12.78±4.10)% vs (12.54±4.24)%] ( P=0.106) for diastolic phase, respectively. The difference in the calculation results of HDF parameters related to ventricular function was not statistically significant (all P>0.05), and there was good consistency ( r=0.924-0.996, ICC=0.924-0.995). The two HDF parameters related to atrial function were sensitive to the measurement method of mitral valve orifice diameter [RMS of longitudinal HDF during active atrial emptying: (3.26±1.51)% vs (3.32±1.55)%, P=0.006; longitudinal HDF pulse during active atrial emptying: (-2.60±1.28)% vs (-2.76±1.30)%, P<0.001]. Conclusions:The ventricular function related HDF parameters obtained from the analysis of mitral valve orifice diameter using single plane and multi plane methods have good consistency, and can be evaluated using relatively simple single plane methods for left ventricular HDF.

Objective:This study investigated the efficacy and safety of denosumab (DENOS) versus zoledronic acid (ZOL) in the bone disease treatment of newly diagnosed multiple myeloma.Methods:The clinical data of 80 patients with myeloma bone disease (MBD) at the Fifth Medical Center of PLA General Hospital between March 1, 2021 and June 30, 2023 were retrospectively reviewed. Eighteen patients with severe renal impairment (SRI, endogenous creatinine clearance rate<30 ml/min) were treated with DENOS, and 62 non-SRI patients were divided into DENOS (30 patients) and ZOL group (32 patients) .Results:Hypocalcemia was observed in 26 (33%) patients, and 22 patients developed hypocalcemia during the first treatment course. The incidence of hypocalcemia in the non-SRI patients of DENOS group was higher than that in the ZOL group [20% (6/30) vs 13% (4/32), P=0.028]. The incidence of hypocalcemia in SRI was 89% (16/18). Multivariate logistic regression analysis revealed that endogenous creatinine clearance rate<30 ml/min was significantly associated with hypocalcemia after DENOS administration ( P<0.001). After 1 month of antiresorptive (AR) drug application, the decrease in the serum β-C-terminal cross-linked carboxy-telopeptide of collagen type I concentrations of SRI and non-SRI patients in the DENOS group were significantly higher than that in the ZOL group (68% vs 59% vs 27%, P<0.001). The increase in serum procollagen type Ⅰ N-terminal propeptide concentrations of patients with or without SRI in the DENOS group were significantly higher than that in the ZOL group (34% vs 20% vs 11%, P<0.05). The level of intact parathyroid hormone in each group increased after AR drug treatment. None of the patients developed osteonecrosis of the jaw and renal adverse events, and no statistically significant differences in the overall response rate, complete remission and stringent complete remission rates were found among the groups ( P>0.05), and the median PFS and OS time were not reached ( P>0.05) . Conclusions:In the treatment of MBD, DENOS minimizes nephrotoxicity and has strong AR effect. Hypocalcemia is a common adverse event but is usually mild or moderate and manageable.

Objectives:To investigate the clinical feasibility of three-dimensional(3D)high-resolution late gadolinium enhancement(LGE)MRI in accessing left atrial myocardial fibrosis in patients with atrial fibrillation(AF). Methods:A total of 34 AF patients referred for hybrid surgical ablation were retrospectively enrolled in this study.3D-LGE-MRI images were acquired by Siemens 3.0 T machine and analyzed by ADAS post-processing software by two experienced radiologists to obtain parameters such as the area and the area percentage of LGE.Regional analysis was performed by one of the two radiologists at ten left atrial segments.The Kappa test was used to assess the agreement for scoring image quality,and the interclass correlation coefficient(ICC)was used to evaluate the interobserver agreement of LGE parameters.The parameters of left atrial morphology,area(and area percentage)of LGE,and location of LGE were compared between patients with persistent AF and paroxysmal AF. Results:Images of all 34 patients were considered to have diagnostic value.The scores of the overall image quality and the clarity of the left atrial wall evaluated by two radiologists were(2.88±0.64)points and(3.26±0.75)points(radiologist 1),(2.97±0.58)points and(3.24±0.70)points(radiologist 2),respectively.The corresponding Kappa values were 0.724 and 0.859.Both the area and the area percentage of LGE showed good consistency among observers,and the ICCs were 0.969 and 0.950,respectively.The difference in the area of LGE and the area percentage of LGE between patients with paroxysmal and persistent atrial fibrillation was similar(both P＞0.05).Compared with patients with paroxysmal AF,patients with persistent AF had a higher Utah stage and more severe myocardial fibrosis in the right inferior pulmonary vein antrum and the left atrial septum(all P＜0.05). Conclusions:3D high-resolution LGE-MRI provides a non-invasive way to visualize and quantify left atrial myocardial fibrosis.The extent of left atrial fibrosis in patients with persistent AF is more severe than that in patients with paroxysmal AF,with a preferential distribution in the right inferior pulmonary vein antrum and the left atrial septum.

Objective To observe the clinical application value of total free-breathing cardiac MR(CMR)examination preliminarily.Methods Two patients who underwent CMR scanning under free-breathing state,including cine,motion correction T1 and T2 mapping,blood flow imaging,and late gadolinium enhancement scanning were retrospectively enrolled,and the qualities of the above images were evaluated and compared with that of conventional CMR images under breath-holding state.Results No significant difference of imaging quality was found between total free-breathing and conventional breath-holding CMR.The differences of left ventricular ejection fraction,cardiac output,left ventricular end-diastolic volume index and left ventricular mass measured based on CMR images under different breath conditions were limited.Conclusion Total free-breathing CMR was feasible in clinical practice,which could provide"one-stop"evaluation of cardiac structure,function and myocardial histological characteristics,hence having promising clinical prospects.

Objective:To investigate the value of T 1ρ mapping in the assessment of myocardial fibrosis in patients with hypertrophic cardiomyopathy (HCM). Methods:Forty HCM patients and 16 healthy volunteers who underwent CMR examination between December 2021 and May 2022 were prospectively enrolled. T 1ρ mapping, pre-and post-contrast T 1 mapping, and gadolinium contrast-enhanced delayed enhancement (LGE) imaging were performed in HCM patients, while T 1ρ mapping and T 1 mapping were performed in volunteers. HCM patients were further divided into LGE-positive (LGE+) and LGE-negative (LGE-) groups based on the presence or absence of LGE. The T 1ρ and pre-contrast T 1 values of the left ventricular myocardium of HCM patients and volunteers were measured, and the extracellular volume fraction (ECV) of the left ventricular myocardium of HCM patients was measured using pre-and post-contrast T 1 mapping. One-way ANOVA was used to compare the T 1ρ and pre-contrast T 1 values among the LGE+, LGE-, and volunteer groups, and pairwise comparisons were further corrected using the Bonferroni method. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performance of pre-contrast T 1 and T 1ρ values in distinguishing LGE+ and LGE- patients from volunteers. The chi-square test or Fisher′s exact probability test was used for categorical variable comparisons. Pearson correlation coefficient was used to evaluate the correlation between T 1ρ and pre-contrast T 1, and ECV. Results:There were no significant differences in age, gender, and body surface area among the LGE+, LGE-, and healthy control groups ( P>0.05). Compared to the HC group, both the T 1ρ value ( t=5.74, P<0.001) and the pre-contrast T 1 value ( t=3.99, P<0.001) increased in LGE positive group, as well as in the LGE negative group (T 1ρ: t=4.19, P<0.001; T 1: t=2.06, P<0.044). ROC analysis showed that the area under the curve (AUC) of T 1ρ and pre-contrast T 1 in distinguishing LGE+patients from healthy controls were 0.93 (sensitivity 84.0%, specificity 93.8%) and 0.87 (sensitivity 84.0%, specificity 87.5%), respectively. The AUC of T 1ρ and pre-contrast T 1 in distinguishing LGE-patients from healthy controls were 0.84 (sensitivity 86.7%, specificity 68.8%) and 0.68 (sensitivity 60%, specificity 68.8%), respectively. The correlation analysis showed that the T 1ρ value of the left ventricular myocardium was positively correlated with the pre-contrast T 1 value ( r=0.31, P=0.02) and ECV value ( r=0.38, P=0.02). Conclusion:Without the use of contrast agents, T 1ρ mapping shows good performance for myocardial replacement fibrosis and diffuse fibrosis in HCM patients.

Objective:To explore the clinical value of cardiac MR (CMR) compression sensing (CS) ultrafast cine sequence in evaluating left and right ventricular systolic function by comparing with traditional segmented acquisition cine sequence (Seg).Methods:Twenty-seven patients with various heart disease were prospectively included. Seg, breath holding CS (bhCS) and free breathing CS (fbCS) covering the left and right ventricles using multi slices in short axis were performed in random order. Friedman test was used to evaluate the overall image quality (grade 1-5 score), blood pool myocardial signal ratio (BMC) and edge sharpness under different methods. Biventricular end diastolic volume (EDV), end systolic volume (ESV), stroke volume (SV), ejection fraction (EF) and left ventricular myocardial mass (Mass) were measured for all three methods. The agreements of the functional measurements between bhCS and Seg (gold standard), and between fbCS and Seg were analyzed by Bland-Altman, and the correlation test was performed.Results:Twenty-four patients with diagnostic images(overall image quality score≥2) for all three methods were included in further analysis. The total imaging time of Seg, bhCS and fbCS decreased successively[375.0 (332.0, 405.6) vs. 50.0 (47.8, 53.7) vs. 20.0 (17.8, 23.7) s, χ 2=48.00, P<0.001]. The overall image quality of fbCS was slightly lower than that of Seg ( Z=-2.67, P=0.023), and there was no difference between Seg and bhCS ( Z=-1.44, P=0.447), bhCS and fbCS ( Z=1.23, P=0.660). There were no differences in edge sharpness (χ 2=1.08, P=0.582) and BMC (χ 2=0.58, P=0.747) for three methods. Bland-Altman polts showed good agreement for biventricular functional measurements between bhCS and Seg, and between fbCS and Seg. All functional measurements of bhCS and fbCS were highly correlated with that of seg ( r>0.96, P<0.001). Conclusions:Compared with traditional sequences, CS ultrafast cine sequences can save scanning time and provide similar image quality. No matter whether breath holding or not, the cardiac functional results of CS sequence and traditional cine sequence have good agreement and high correlation.

In vitro studies have established the prevalent theory that the mitochondrial kinase PINK1 protects neurodegeneration by removing damaged mitochondria in Parkinson's disease (PD). However, difficulty in detecting endogenous PINK1 protein in rodent brains and cell lines has prevented the rigorous investigation of the in vivo role of PINK1. Here we report that PINK1 kinase form is selectively expressed in the human and monkey brains. CRISPR/Cas9-mediated deficiency of PINK1 causes similar neurodegeneration in the brains of fetal and adult monkeys as well as cultured monkey neurons without affecting mitochondrial protein expression and morphology. Importantly, PINK1 mutations in the primate brain and human cells reduce protein phosphorylation that is important for neuronal function and survival. Our findings suggest that PINK1 kinase activity rather than its mitochondrial function is essential for the neuronal survival in the primate brains and that its kinase dysfunction could be involved in the pathogenesis of PD.

Animal models are essential for investigating the pathogenesis and developing the treatment of human diseases. Identification of genetic mutations responsible for neurodegenerative diseases has enabled the creation of a large number of small animal models that mimic genetic defects found in the affected individuals. Of the current animal models, rodents with genetic modifications are the most commonly used animal models and provided important insights into pathogenesis. However, most of genetically modified rodent models lack overt neurodegeneration, imposing challenges and obstacles in utilizing them to rigorously test the therapeutic effects on neurodegeneration. Recent studies that used CRISPR/Cas9-targeted large animal (pigs and monkeys) have uncovered important pathological events that resemble neurodegeneration in the patient's brain but could not be produced in small animal models. Here we highlight the unique nature of large animals to model neurodegenerative diseases as well as the limitations and challenges in establishing large animal models of neurodegenerative diseases, with focus on Huntington disease, Amyotrophic lateral sclerosis, and Parkinson diseases. We also discuss how to use the important pathogenic insights from large animal models to make rodent models more capable of recapitulating important pathological features of neurodegenerative diseases.
Amyotrophic Lateral Sclerosis/genetics* ; Animals ; Brain/pathology* ; Disease Models, Animal ; Gene Editing ; Neurodegenerative Diseases/pathology* ; Swine

Objective:To explore the clinical value of T 1 mapping/indexed extracellular volume fraction (iECV) quantified with cardiac MR (CMR) parameters, and its correlation with traditional indicators of myocardial dysfunction in aortic insufficiency (AI) patients. Methods:A total of 36 patients clinically and radiologically diagnosed with chronic AI in our hospital between May 2012 and February 2016 were retrospectively selected. All AI patients underwent conventional CMR protocol, native and post T 1 mapping. CMR parameters, such as aortic regurgitant fraction (RF), late gadolinium enhancement (LGE) mass fraction, myocardial extracellular volume fraction (ECV) and iECV. Based on the values of aortic RF, AI patients were divided into mild AI group (9 cases), moderate AI group (14 cases) and severe AI group (13 cases). The clinical characteristics were teased from the patients′ electronic medical records. Univariate analysis of variance was used to compare the measurement data of native T 1 mapping, post-contrast T 1 mapping, ECV, and iECV. LSD test was used for pair wise comparison between the mild AI, moderate AI and severe AI groups. Data about cardiovascular history, New York Heart Association (NYHA) heart function classification, and LGE were compared by chi-square test or Fisher exact test. The correlation between left ventricle ejection fraction (LVEF) and iECV was evaluated by Spearman correlation analysis. Results:There was no difference in age, sex, cardiovascular history among the three groups. Comparison of patients with different severity of AI in the three groups: (1) There was statistically significant difference in the LGE positive rate among the three groups ( P=0.023), while the myocardial replacement of fibrosis increased with the grade of aortic regurgitation. (2) There was no statistically significant difference in the measurement data of native T 1 mapping, post-contrast T 1 mapping, ECV among the three groups ( H=1.815, 0.929, 2.496, all P values>0.05), while the diffuse myocardial fibrosis tended to increase with the degree of aortic regurgitation. There was statistically significant difference in iECV among the three groups ( H=16.725, P<0.001). The measurement data of iECV in the severe AI group was significantly higher than those in the other two groups ( P<0.05). LVEF value was inversely correlated with iECV ( r=-0.649, P<0.001). Conclusions:Quantitative T 1 mapping/iECV can serve as a parameter to noninvasively identify diffuse myocardial fibrosis in AI patients of different severities. It changes with LVEF and can manifest the reversible stage of left ventricular decompensation.

OBJECTIVE: Segmented cardiac cine magnetic resonance imaging (MRI) is the gold standard for cardiac ventricular volumetric assessment. In patients with difficulty in breath-holding or arrhythmia, this technique may generate images with inadequate quality for diagnosis. Real-time cardiac cine MRI has been developed to address this limitation. We aimed to assess the performance of retrospective electrocardiography-gated real-time cine MRI at 3T for left ventricular (LV) volume and mass measurement. MATERIALS AND METHODS: Fifty-one patients were consecutively enrolled. A series of short-axis cine images covering the entire left ventricle using both segmented and real-time balanced steady-state free precession cardiac cine MRI were obtained. End-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF), and LV mass were measured. The agreement and correlation of the parameters were assessed. Additionally, image quality was evaluated using European CMR Registry (Euro-CMR) score and structure visibility rating. RESULTS: In patients without difficulty in breath-holding or arrhythmia, no significant difference was found in Euro-CMR score between the two techniques (0.3 ± 0.7 vs. 0.3 ± 0.5, p > 0.05). Good agreements and correlations were found between the techniques for measuring EDV, ESV, EF, SV, and LV mass. In patients with difficulty in breath-holding or arrhythmia, segmented cine MRI had a significant higher Euro-CMR score (2.3 ± 1.2 vs. 0.4 ± 0.5, p < 0.001). CONCLUSION: Real-time cine MRI at 3T allowed the assessment of LV volume with high accuracy and showed a significantly better image quality compared to that of segmented cine MRI in patients with difficulty in breath-holding and arrhythmia.
Arrhythmias, Cardiac ; Diagnosis ; Heart Ventricles ; Humans ; Magnetic Resonance Imaging ; Magnetic Resonance Imaging, Cine* ; Retrospective Studies* ; Stroke Volume