TRAF Family Member 4 Promotes Cardiac Hypertrophy Through the Activation of the AKT Pathway.

Background Pathological cardiac hypertrophy is a major cause of heart failure morbidity. The complex mechanism of intermolecular interactions underlying the pathogenesis of cardiac hypertrophy has led to a lack of development and application of therapeutic methods. Methods and Results Our study provides the first evidence that TRAF4, a member of the tumor necrosis factor receptor-associated factor (TRAF) family, acts as a promoter of cardiac hypertrophy. Here, Western blotting assays demonstrated that TRAF4 is upregulated in cardiac hypertrophy. Additionally, TRAF4 deletion inhibits the development of cardiac hypertrophy in a mouse model after transverse aortic constriction surgery, whereas its overexpression promotes phenylephrine stimulation-induced cardiomyocyte hypertrophy in primary neonatal rat cardiomyocytes. Mechanistically, RNA-seq analysis revealed that TRAF4 promoted the activation of the protein kinase B pathway during cardiac hypertrophy. Moreover, we found that inhibition of protein kinase B phosphorylation rescued the aggravated cardiomyocyte hypertrophic phenotypes caused by TRAF4 overexpression in phenylephrine-treated neonatal rat cardiomyocytes, suggesting that TRAF4 may regulate cardiac hypertrophy in a protein kinase B-dependent manner. Conclusions Our results revealed the regulatory function of TRAF4 in cardiac hypertrophy, which may provide new insights into developing therapeutic and preventive targets for this disease.

The Role of Structural Deterioration and Biomechanical Changes of the Necrotic Lesion in Collapse Mechanism of Osteonecrosis of the Femoral Head.

Osteonecrosis of the femoral head (ONFH) is a crippling disease which is due to a lack of effective therapeutic measures. Its natural progression is rapid, the internal bone structure of the femoral head changes dramatically, and the subsequent fractures and collapse cause severe hip pain and loss of hip function. Femoral head collapse is a critical turning point in the development of ONFH and is related to the prognosis of patients. Early prevention and intervention help to preserve the hip joint and delay femoral head collapse. However, the mechanism of collapse still needs to be further studied because it is affected by different complex factors. This review discusses the underlying causes of femoral head collapse from two aspects: structural degradation and regional changes of biomechanical properties in the necrotic femoral head.

Hydrogel composite scaffolds achieve recruitment and chondrogenesis in cartilage tissue engineering applications.

BACKGROUND: The regeneration and repair of articular cartilage remains a major challenge for clinicians and scientists due to the poor intrinsic healing of this tissue. Since cartilage injuries are often clinically irregular, tissue-engineered scaffolds that can be easily molded to fill cartilage defects of any shape that fit tightly into the host cartilage are needed. METHOD: In this study, bone marrow mesenchymal stem cell (BMSC) affinity peptide sequence PFSSTKT (PFS)-modified chondrocyte extracellular matrix (ECM) particles combined with GelMA hydrogel were constructed. RESULTS: In vitro experiments showed that the pore size and porosity of the solid-supported composite scaffolds were appropriate and that the scaffolds provided a three-dimensional microenvironment supporting cell adhesion, proliferation and chondrogenic differentiation. In vitro experiments also showed that GelMA/ECM-PFS could regulate the migration of rabbit BMSCs. Two weeks after implantation in vivo, the GelMA/ECM-PFS functional scaffold system promoted the recruitment of endogenous mesenchymal stem cells from the defect site. GelMA/ECM-PFS achieved successful hyaline cartilage repair in rabbits in vivo, while the control treatment mostly resulted in fibrous tissue repair. CONCLUSION: This combination of endogenous cell recruitment and chondrogenesis is an ideal strategy for repairing irregular cartilage defects.

Core Decompression with Local Administration of Zoledronate and Enriched Bone Marrow Mononuclear Cells for Treatment of Non-Traumatic Osteonecrosis of Femoral Head.

OBJECTIVE: To investigate the efficacy and safety of core decompression (CD) with local administration of zoledronate and enriched bone marrow mononuclear cells (BMMCS) for the treatment of non-traumatic osteonecrosis of femoral head (ONFH). METHODS: A total of 17 patients (30 hips) diagnosed with stage II and III ONFH according to the 2019 revised Association for Research on Osseous Circulation (ARCO) staging criteria from 2012 to 2014 were retrospectively reviewed. The patients received the following therapy: the BMMCs and zoledronate were injected into the necrotic zone, respectively, along with CD. The mean age of the patients was 36.8 years; 14 were men and three were women. All patients included had non-traumatic ONFH and a minimum follow-up of 5 years, which ended when total hip arthroplasty (THA) was performed. Imaging modalities, including plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI) were taken pre- and postoperatively. Harris hip score (HHS) was used to evaluate the functional outcomes of femoral head necrosis. Kaplan-Meier analysis was adopted to determine the probability of survivorship with THA as the end point in this series of patients. The correlation between radiological progression or THA and related risk factors were further analyzed. All complications were recorded. RESULTS: With THA as the follow-up endpoint, All patients were followed up for an average of 69.1 ± 20.5 months (range, 18-95 months). Preoperative imaging found six hips (20%) at ARCO stage II, 14 hips (46.7%) at stage IIIA, 10 hips (33.3%) at stage IIIB. Fourteen hips (46.7%) shown progression radiologically, while six hips (20%) underwent TKA among these patients with hip preservation. The cumulative survival was 80% (95% CI, 0.608-905) at 5 years with THA as the end point. HHS improved from 63.3 ± 8.7 preoperatively to 74.6 ± 20.6 postoperatively (P = 0.000). Radiological progression was found to be associated with ARCO stage, Japanese Investigation Committee (JIC) type, and corticosteroid exposure (P = 0.047; P = 0.012; P = 0.031). However, no correlation was found between conversion to THA and the known risk factors. No major complication was reported, with only four patients complaining about general weakness and muscle soreness, and all disappeared within 2-3 days. CONCLUSIONS: The novel treatment modality could relieve pain, delay the progression of collapse, which might be an effective and safe method for hip preservation of early and mid-term ONFH. However, the effect of this method may be related to ARCO stage, JIC type, and corticosteroid exposure.

Three-Dimensional Distribution of Bone-Resorption Lesions in Osteonecrosis of the Femoral Head Based on the Three-Pillar Classification.

OBJECTIVE: To investigate three-dimensional distribution of bone-resorptive lesions based on the three-pillar classification and its effect on the disease progression of osteonecrosis of the femoral head (ONFH). METHODS: A total of 194 femoral head CT images from 117 patients diagnosed with ARCO stage II and III ONFH were retrospectively reviewed from April 2014 to February 2019. Three-dimensional structures of the femoral head and the bone-resorptive lesions were reconstructed. Using the three-pillar classification and coronal plane of the femoral head, we divided each femoral head into six regions to observe the location characteristics of bone-resorption lesions, and explore the destruction of different areas of the femoral head by the bone-resorptive lesions. Then the hips were divided into two groups based on whether they contained bone-resorption lesions and compared the difference of stage II and stage III between the two groups. RESULTS: The regional distribution revealed 39 (27.27%), 55 (38.46%), six (4.20%), 23 (16.08%), 17 (11.89%) and three (2.10%) bone-resorptive lesions in regions I, II, III, IV, V and VI respectively. The lateral pillar, AL (I + IV), contained 44.76% of the lesions, central pillar, C (II + V), 48.95%, and medial pillar, M (III + VI), 6.29%. Moreover, there were 81.82% bone-resorption lesions in anterolateral pillar, AL (I + II + IV), and 18.18% in posteromedial pillar, PM (III + V + VI). In all ONFH hips, the lateral pillar of 81(88.04%) femoral heads were affected, the central pillar of 84 (91.30%) femoral heads were affected, and the medical pillar of 29 (31.52%) femoral heads were affected. The ratio of ARCO stage III in the group with bone-resorption lesions was significantly higher than that of the group without bone-resorption lesions (76.09% vs 30.39%, P < 0.001). CONCLUSIONS: This study demonstrated that the bone-resorption lesions are mainly distributed in the lateral and central pillar of the femoral head, and the two pillars of the femoral head are usually involved by bone-resorption lesions. Furthermore, the ratio of ARCO stage III in the group with bone-resorption lesions was significantly higher than that of the group without bone-resorption lesions, suggesting that the bone-resorption lesions might accelerate the progression of ONFH.

Prevalence and modifiable risk factors of degenerative valvular heart disease among elderly population in southern China.

OBJECTIVE: To investigate the prevalence and modifiable risk factors of degenerative valvular heart disease (DVHD) among elderly population in southern China. METHODS: A stratified multistage sampling method was used to recruit subjects. The contents of the survey included the questionnaire, laboratory examination, echocardiography, and other auxiliary examinations. The possible risk factors of DVHD were analyzed by logistic regression analysis. RESULTS: A total of 3538 subjects ≥ 65 years of age were enrolled. One thousand three hundred and seven subjects (36.9%) were diagnosed with DVHD. Degenerative was the most common etiology of VHD. Prevalence of DVHD increased with advancing age. The prevalence of DVHD differed by living region (χ 2 = 45.594, P < 0.001), educational level ( χ 2 = 50.557, P < 0.001), and occupation ( χ 2 = 36.961, P < 0.001). Risk factors associated with DVHD included age (two-fold increased risk for each 10-year increase in age), elevated level C-reactive protein (OR = 1.346, 95% CI: 1.100-1.646), elevated level low density lipoprotein (OR = 1.243, 95% CI: 1.064-1.451), coronary artery disease (OR = 1.651, 95% CI: 1.085-2.513), smoking (OR = 1.341, 95% CI: 1.132-1.589), and hypertension (OR = 1.414, 95% CI: 1.221-1.638). Other significant risk factors included reduced or elevated level red blood cell (OR = 1.347, 95% CI: 1.031-1.761; OR = 1.599, 95% CI: 1.097-2.331; respectively), elevated level platelets (OR = 1.891, 95% CI: 1.118-3.198), elevated level uric acid (OR = 1.282, 95% CI: 1.112-1.479), and stroke (OR: 1.738, 95% CI = 1.085-2.513). CONCLUSIONS: The survey characterized the baseline conditions of DVHD cohort of elderly population in Guangzhou city. The established and emerging risk factors for DVHD may represent challenges and opportunities for therapy.

Local administration of zoledronic acid prevents traumatic osteonecrosis of the femoral head in rat model.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a refractory disease due to its unclear pathomechanism. Neither conservative treatment nor surgical treatment during the early stage of ONFH achieves satisfactory results. Therefore, this study aims to explore the available evidence on the effect of zoledronic acid on early-stage ONFH. METHODS: For groups were established:the Normal group, model group, Normal saline group(NS group) and zoledronic acid-treated group. The blood supply to the femoral head of animals in the model group and zoledronic acid-treated group was interrupted via a surgical procedure, and zoledronic acid was then locally administered to the femoral head. Four weeks after surgery, all the hips were harvested and evaluated by micro-CT and histopathology(H&E staining, TRAP staining, Toluidine blue staining and masson staining). RESULTS: The values of BMD, BS/BV and Tb.Th in the Normal group and zoledronic acid-treated group were significantly higher than those in the model group and NS group (p â€‹< â€‹0.05). The outcome of H&E staining, Toluidine blue staining and masson staining were consistent with that of micro-CT. CONCLUSION: The local administration of zoledronic acid in the femoral head had positive effects on the bone structure of the femoral head in a modified rat model of traumatic ONFH and offered a promising therapeutic strategy during the early stage of ONFH. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This article could provide a choice for treating patients who have osteonecrosis of femora head and can be the basic research for advanced development over this disease.

Effect of micronutrient pack on micronutrient status and antioxidant capacities among institutional older adults in Shanghai, China.

BACKGROUND AND OBJECTIVES: Older adults are at increased risk of micronutrient deficiency, disrupting the balance of oxidation/antioxidation system and leading to serious health burdens. This study aimed to investigate the effect of micronutrient pack on micronutrient status and oxidative/antioxidative biomarkers in institutional older adults. METHODS AND STUDY DESIGN: Subjects aged 65-100 years were randomly assigned to either intervention group or control group (n=49 each), providing a package of micronutrient pack or placebo daily for three months. The concentrations of micronutrients, malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were detected both at baseline and at the end of the study. RESULTS: The changes in concentrations of serum folate (21.1±1.6 vs 0.6±0.5 nmol/L), vitamin B-1 (3.4±0.4 vs -0.2±0.3 nmol/L), vitamin B-2 (11.5±3.3 vs 2.3±1.4 nmol/L), vitamin B-12 (128.8±34.8 vs 13.3±16.0 pmol/L), 25-hydroxyvitamin D (17.8±1.3 vs -0.8±0.5 ng/mL) and plasma zinc (0.6±1.8 vs -9.6±1.9 µmol/L) over 3-months were significantly increased in the intervention group compared with the control group (all p<0.05). While the prevalence of folate, vitamin B-12 and vitamin D deficiencies were significantly decreased after 3-months intervention (all p<0.05). Moreover, changes in serum MDA level (-1.5±0.2 vs 0.2±0.3 nmol/mL) were remarkably reduced, and the activities of serum GSH-Px (1.3±0.3 vs 0.3±0.2 ng/mL) and plasma SOD (14.3±2.4 vs -2.1±2.4 U/mL) were increased in the intervention group than those of in the control group (all p<0.01). CONCLUSIONS: The micronutrient pack among institutional older adults was well-accepted with good compliance and tolerance. The 3-month intervention may improve micronutrient status and enhance antioxidative capacities.

Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease.

Sickle cell disease (SCD) results from a point mutation in the ß-globin gene forming hemoglobin S (HbS), which polymerizes in deoxygenated erythrocytes, triggering recurrent painful vaso-occlusive crises and chronic hemolytic anemia. Reactivation of fetal Hb (HbF) expression ameliorates these symptoms of SCD. Nuclear factor (erythroid derived-2)-like 2 (Nrf2) is a transcription factor that triggers cytoprotective and antioxidant pathways to limit oxidative damage and inflammation and increases HbF synthesis in CD34+ stem cell-derived erythroid progenitors. We investigated the ability of dimethyl fumarate (DMF), a small-molecule Nrf2 agonist, to activate γ-globin transcription and enhance HbF in tissue culture and in murine and primate models. DMF recruited Nrf2 to the γ-globin promoters and the locus control region of the ß-globin locus in erythroleukemia cells, elevated HbF in SCD donor-derived erythroid progenitors, and reduced hypoxia-induced sickling. Chronic DMF administration in SCD mice induced HbF and increased Nrf2-dependent genes to detoxify heme and limit inflammation. This improved hematological parameters, reduced plasma-free Hb, and attenuated inflammatory markers. Chronic DMF administration to nonanemic primates increased γ-globin mRNA in BM and HbF protein in rbc. DMF represents a potential therapy for SCD to induce HbF and augment vasoprotection and heme detoxification.

Sequencing and analysis of JC virus DNA from natalizumab-treated PML patients.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) in natalizumab-treated MS patients is linked to JC virus (JCV) infection. JCV sequence variation and rearrangements influence viral pathogenicity and tropism. To better understand PML development, we analyzed viral DNA sequences in blood, CSF and/or urine of natalizumab-treated PML patients. METHODS: Using biofluid samples from 17 natalizumab-treated PML patients, we sequenced multiple isolates of the JCV noncoding control region (NCCR), VP1 capsid coding region, and the entire 5 kb viral genome. RESULTS: Analysis of JCV from multiple biofluids revealed that individuals were infected with a single genotype. Across our patient cohort, multiple PML-associated NCCR rearrangements and VP1 mutations were present in CSF and blood, but absent from urine-derived virus. NCCR rearrangements occurred in CSF of 100% of our cohort. VP1 mutations were observed in blood or CSF in 81% of patients. Sequencing of complete JCV genomes demonstrated that NCCR rearrangements could occur without VP1 mutations, but VP1 mutations were not observed without NCCR rearrangement. CONCLUSIONS: These data confirm that JCV in natalizumab-PML patients is similar to that observed in other PML patient groups, multiple genotypes are associated with PML, individual patients appear to be infected with a single genotype, and PML-associated mutations arise in patients during PML development.

[Clinical observation of electrocardiographic changes in response to taxotere combined with adriamycin treatment for breast cancer].

OBJECTIVE: To study the effects of taxotere and adriamycin based chemotherapy on the electrocardiogram (ECG) of patients with locally advanced or metastatic breast cancer. METHODS: Chemotherapy combining taxotere (75 mg/m(2)) and adriamycin (5 mg/m(2)) once every 3 weeks was performed in 250 patients with locally advanced or metastatic breast cancer. Electrocardiograph was recorded before and after each treatment course for a total of 10 courses. RESULTS: After the completion of the 10 treatment courses, 8 (3.2%) patients had accelerated heart rate, 12 presented low voltage of QRS complex in the limb leads, and Q-T interval extension, ST segment depression, T-wave flattening, T-wave inversion occurred in 28, 18, 29, and 12 patients, respectively. The rest patients had no ECG changes. CONCLUSIONS: Taxotere and adriamycin as antitumor chemotherapeutic drugs may cause toxicity in the heart, and result in pericardial effusion, myocardial injury, chronic myocardial ischemia or hypoxia that may lead to abnormal changes in QRS complex and ST-T segment in ECG.

Tumor suppressor gene p16 and Rb expression in gastric cardia precancerous lesions from subjects at a high incidence area in northern China.

AIM: To further understand the molecular basis for gastric cardia carcinogenesis and to provide etiological clues. METHODS: Endoscopic mucosa biopsy and histopathological examinations were made on 37 subjects from a high incidence area for both esophageal and gastric cardia carcinomas in northern China. All the biopsy samples were fixed in 850 ml. (-1)L alcohol and embedded in paraffin. Each block contained one piece of tissue and was serially section at 5 microm. Immunohistochemistry (ABC) was carried out on these gastric cardia samples to determine the alterations of p16 and Rb. RESULTS: Based on the histopathlogical examination there were 11 cases of chronic superficial gastritis, 12 cases of chronic atrophic gastritis and 14 cases of dysplasia. The immunostaining demonstrated different levels of unclear immunostaining of p16 and Rb in normal gastric cardia tissue and the tissues with different severity of lesions. With the lesions progressing, the positive immunostaining rates for p16 protein had a decreasing tendency. In contrast, the positive immunostaining rate for Rb protein had an increasing tendency. There was a significant negative relationship between the two parameters. Changes of p16 was CSG 11(100%), CAG 7(58%), DYS 4(29%) and changes of Rb was CSG 2(18%), CAG 8(67%) and DYS 12(86%), (P<0.05). CONCLUSION: The alterations of p16 and Rb protein may play a role in the early stages of gastric cardia carcinogenesis.