Interaction of age and CYP2C19 genotypes on voriconazole steady-state trough concentration in Chinese patients.

OBJECTIVES: Both age and CYP2C19 genotypes affect voriconazole plasma concentration; the interaction of age and CYP2C19 genotypes on voriconazole plasma concentration remains unknown. This study aims to investigate the combined effects of age and CYP2C19 genotypes on voriconazole plasma concentration in Chinese patients. METHODS: A total of 480 patients who received voriconazole treatment were recruited. CYP2C19*2 (rs4244285) and CYP2C19*3 (rs4986893) polymorphisms were genotyped. Patients were divided into the young and the elderly groups by age of 60 years old. Influence of CYP2C19 genotype on steady-state trough concentration (Css-min) in overall patients and in age subgroups was analyzed. RESULTS: Voriconazole Css-min correlated positively with age, and mean voriconazole Css-min was significantly higher in the elderly group (P < 0.001). CYP2C19 poor metabolizers showed significantly increased mean voriconazole Css-min in the young but not the elderly group. The percentage of patients with subtherapeutic voriconazole Css-min (<1.0 mg/l) was higher in the young group and that of supratherapeutic voriconazole Css-min (>5.5 mg/l) was higher in the elderly patients. When the average Css-min in the CYP2C19 normal metabolizer genotype was regarded as a reference, CYP2C19 genotypes showed greater impact on voriconazole Css-min in the young group, while the influence of age on voriconazole Css-min exceeded CYP2C19 genotypes in the elderly. CONCLUSION: CYP2C19 genotypes affects voriconazole exposure is age dependent. Influence of CYP2C19 poor metabolizer genotype on increased voriconazoleexposure is prominent in the young, while age is a more important determinant factor for increased voriconazole exposure in the elderly patients.

Dynamics of anti-SARS-CoV-2 IgG antibody responses following breakthrough infection and the predicted protective efficacy: A longitudinal community-based population study in China.

OBJECTIVES: To assess the dynamics of the anti-SARS-CoV-2 IgG antibody levels and their efficacy against COVID-19. METHODS: We conducted a longitudinal serological analysis of 852 breakthrough COVID-19 infections among the community-based population in Yichang, China. Anti-SARS-CoV-2 IgG levels were measured by chemiluminescence at approximately 3, 4, and 9 months after infection. A linear mixed model predicted IgG antibody decline over 18 months. The effectiveness of antibodies in preventing symptomatic and severe infections was determined using an existing meta-regression model. RESULTS: IgG antibodies slowly declined after breakthrough infections. Initially high at around 3 months (339.44 AU/mL, IQR: 262.78-382.95 AU/mL), levels remained significant at 9 months (297.74 AU/mL, IQR: 213.22-360.62 AU/mL). The elderly (≥60 years) had lower antibody levels compared to the young (<20 years) (P < 0.001). The protective efficacy of antibodies against symptomatic and severe infections was lower in the elderly (≥60 years) (78.34% and 86.33%) compared to the young (<20 years) (96.56% and 98.75%) after 1 year. CONCLUSION: The study indicated a slow decline in anti-SARS-CoV-2 IgG antibodies, maintaining considerable efficacy for over 1 year. However, lower levels in the elderly suggest reduced protective effects, underscoring the need for age-specific vaccination strategies.

Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profile.

BACKGROUND: Targeting CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Despite the encouraging clinical efficacy observed in hematologic malignancies through CD47-SIRPα blockade, there are safety concerns related to the binding of anti-CD47 antibodies to CD47 on the membrane of peripheral blood cells. METHODS: In order to enhance the selectivity and therapeutic efficacy of the antibody, we developed a humanized anti-CD47 monoclonal antibody called Gentulizumab (GenSci059). The binding capacity of GenSci059 to CD47 was evaluated using flow cytometry and surface plasmon resonance (SPR) methods, the inhibitory effect of GenSci059 on the CD47-SIRPα interaction was evaluated through competitive ELISA assays. The anti-tumor activity of GenSci059 was assessed using in vitro macrophage models and in vivo patient-derived xenograft (PDX) models. To evaluate the safety profile of GenSci059, binding assays were conducted using blood cells. Additionally, we investigated the underlying mechanisms contributing to the weaker binding of GenSci059 to erythrocytes. Finally, toxicity studies were performed in non-human primates to assess the potential risks associated with GenSci059. RESULTS: GenSci059 displayed strong binding to CD47 in both human and monkey, and effectively inhibited the CD47-SIRPα interaction. With doses ranging from 5 to 20 mg/kg, GenSci059 demonstrated potent inhibition of the growth of subcutaneous tumor with the inhibition rates ranged from 30.3% to complete regression. Combination of GenSci059 with 2.5 mg/kg Rituximab at a dose of 2.5 mg/kg showed enhanced tumor inhibition compared to monotherapy, exhibiting synergistic effects. GenSci059 exhibited minimal binding to hRBCs compared to Hu5F9-G4. The binding of GenSci059 to CD47 depended on the cyclization of N-terminal pyroglutamic acid and the spatial conformation of CD47, but was not affected by its glycosylation modifications. A maximum tolerated dose (MTD) of 450 mg/kg was observed for GenSci059, and no significant adverse effects were observed in repeated dosages up to 10 + 300 mg/kg, indicating a favorable safety profile. CONCLUSION: GenSci059 selectively binds to CD47, effectively blocks the CD47/SIRPα axis signaling pathway and enhances the phagocytosis effects of macrophages toward tumor cells. This monoclonal antibody demonstrates potent antitumor activity and exhibits a favorable safety profile, positioning it as a promising and effective therapeutic option for cancer.

GAS5 promotes cytarabine induced myelosuppression via inhibition of hematopoietic stem cell differentiation.

Cytarabine (Ara-C) is widely used in the induction chemotherapy for acute myeloid leukemia (AML). Association between LncRNA GAS5 genetic polymorphism and the recovery of hematopoietic function after Ara-C-based chemotherapy is observed. This study aimed to identify whether intervention of GAS5 expression and GAS5 genotype affect Ara-C-induced inhibition of hematopoietic stem cells (HSCs) differentiation. In this study, cord blood-derived CD34+ cells were cultured in vitro, and a cell model of myelosuppression was established by treatment of CD34+ cells with Ara-C. The effect of GAS5 overexpression, Ara-C treatment, and GAS5 rs55829688 genotype on the hematopoietic colony-forming ability of CD34+ cells was assessed using methylcellulose-based colony forming unit assay. GAS5 overexpression slowed down the proliferation of cord blood-derived CD34+ cells significantly (p < 0.05) and decreased their ability to form hematopoietic colonies in vitro. Ara-C significantly reduced the hematopoietic colony-forming ability of CD34+ cells in vitro (p < 0.0001), and overexpressing GAS5 further decreased the number of hematopoietic colonies. GAS5 expression was higher in CD34+ cells than in CD34- cells, and positively correlated with GATA1 mRNA expression in CD34+ cells in vitro culture. However, GAS5 genotype had no effect on the total number of hematopoietic colonies formed from cord blood-derived CD34+ cells. In conclusion, our study highlights that GAS5 inhibited the in vitro proliferation and reduced the hematopoietic colony-forming ability of cord blood-derived CD34+ cells, with the most pronounced effect observed on CFU-GEMM formation. GAS5 also enhanced the inhibitory effect of Ara-C on the in vitro hematopoietic ability of CD34+ HSCs.

Design and synthesis of oridonin derivatives as cytotoxic agents.

Oridonin is one of the ent-kaurane diterpenes that have been studied extensively for various bioactivities. In an effort to expand natural scaffold-based library as anticancer agents, we have designed and synthesised a number of novel oridonin derivatives and evaluated their bioactivities on a panel of human cancer cell lines (HCT116, A375, MCF-7, HepG2, and A549). Compound 4b bearing a 4-fluorophenyl moiety was found to be the most active compound with an IC50 value of 0.3 µM against MCF-7 cells, which was 7.4-fold more active than oridonin. This study could provide some insightful information for further synthesis of oridonin derivatives as anticancer agents.

Isolation and Anticancer Progression Evaluation of the Chemical Constituents from Bridelia balansae Tutcher.

The dichloromethane extract of the roots of Bridelia balansae Tutcher (Phyllanthaceae) was found to show potential anticancer activity against HCT116 colorectal cancer cell. Our bioassay-guided phytochemical investigation of the roots of B. balansae led to the identification of 14 compounds including seven lignans (1-7), three phenylbenzene derivatives (8-10), two flavanone (11-12), and two triterpenoids (13-14). Among them, 4'-demethyl-4-deoxypodophyllotoxin (1) is the first aryltetralin lignan compound identified from this plant species. In addition, the stereochemistry of 1 was validated by X-ray crystallography for the first time, and its distinguished cytotoxic effect on HCT116 cells with an IC50 value at 20 nM was induced via an apoptosis induction mechanism. Compound 1 could also significantly decrease the migration rate of HCT116 cells, indicating its potential application against cancer metastasis. The western blot analysis showed that 1 has the potential to inhibit cell proliferation and metastasis. Treatment of 1 resulted in the downregulation of matrix metalloproteinases 2 (MMP2) and p-Akt, while p21 was upregulated. Collectively, the present study on the phytochemical and biological profile of B. balansae has determined the plant as a useful source to produce promising anticancer lead compounds.

Dihydro-Resveratrol Attenuates Oxidative Stress, Adipogenesis and Insulin Resistance in In Vitro Models and High-Fat Diet-Induced Mouse Model via AMPK Activation.

Management of obesity has become a prevalent strategy for preventing the diseases closely integrated with excess body weight such as diabetes over the last half century. Searching for therapeutic agents acting on oxidative stress, adipogenesis and insulin resistance is considered as an efficient approach to control obesity-related diseases. The present study was designed to examine the in vitro and in vivo effects of dihydro-resveratrol (DR2), a naturally occurring compound from Dendrobium medicinal plants, on oxidative stress aggravation, adipogenesis, lipogenesis and insulin sensitivity. We utilized an in vitro 3T3-L1 adipocyte differentiation model to show that DR2 could reduce pre-adipocyte maturation by activation of AMPK/SIRT1 signaling proteins to inhibit p38MAPK proteins. With the use of in vitro oxidative-stress-induced hepatocytes and myoblasts models, DR2 was also shown to be able to reduce oxidative stress aggravation through mediation of Nrf2-related antioxidative cascade, reduce intracellular lipid accumulation through phosphorylation of ACC protein, reduce lipid peroxidation in hepatocytes and promote insulin sensitivity via activation of AKT protein in the insulin-resistant HepG2 cells and C2C12 cells. The effects of DR2 on adipogenesis, lipid accumulation, insulin resistance and blood glucose clearance were further demonstrated in the high-fat diet-induced obesity mouse model. Our in vitro and in vivo studies determined that DR2 could contain therapeutic potential for the treatment of obesity and type 2 diabetes.

Natural Compounds Targeting the Autophagy Pathway in the Treatment of Colorectal Cancer.

Autophagy is a highly conserved intracellular degradation pathway by which misfolded proteins or damaged organelles are delivered in a double-membrane vacuolar vesicle and finally degraded by lysosomes. The risk of colorectal cancer (CRC) is high, and there is growing evidence that autophagy plays a critical role in regulating the initiation and metastasis of CRC; however, whether autophagy promotes or suppresses tumor progression is still controversial. Many natural compounds have been reported to exert anticancer effects or enhance current clinical therapies by modulating autophagy. Here, we discuss recent advancements in the molecular mechanisms of autophagy in regulating CRC. We also highlight the research on natural compounds that are particularly promising autophagy modulators for CRC treatment with clinical evidence. Overall, this review illustrates the importance of autophagy in CRC and provides perspectives for these natural autophagy regulators as new therapeutic candidates for CRC drug development.

[Clinical effect of Corail femoral prosthesis with different offset in total hip arthroplasty].

OBJECTIVE: To explore the early clinical efficacy of primary total hip arthroplasty(THA) with Corail standard stems (KS type) and high offset stems (KHO type), by analyzing the postoperative radiographic parameters of different offset of femoral components with Corail stem which has a neck-shaft angle of 135 ° in unilateral primary THA, by comparing the measurement results on both sides and analyzing the reconstruction of the postoperative femoral offset and the hip joint function recovery. METHODS: A retrospective analysis was made of 186 patients with unilateral hip joint lesions who underwent the first total hip arthroplasty with Johnson & Johnson Corail prostheses from January 2015 to June 2017. According to the use of femoral prostheses with different eccentricities during the operation, the patients were divided into high eccentricity group and standard eccentricity group. In the high eccentricity group, there were 52 cases of Corail high eccentricity prosthesis(KHO type), including 20 females and 32 males;aged 21 to 71 years old with an average of(50.6±13.2) years;body mass index(BMI) was (26.0±4.1) kg/m2. The standard eccentricity group included 134 Corail standard femoral stem prostheses(KS type), 57 females and 77 males;aged 18 to 77 years old with an average of (47.3±14.0) years;BMI was (25.3±3.5) kg/m2. The abduction arm, femoral eccentricity, acetabular eccentricity and the length difference of lower limbs were measured on the postoperatively positive X-ray film of the hip joint. Harris score and related complications were recorded before and after the operation, and the stability of the prosthesis was analyzed. RESULTS: There were significant differences in femoral eccentricity, joint eccentricity and abduction arm between the affected side and the healthy side in the high eccentricity group(P<0.05). There were significant differences in femoral eccentricity and acetabular eccentricity between the affected side and the healthy side in the standard eccentricity group(P<0.05). There were significant differences in combined eccentricity, abduction arm and length of lower limbs between two groups(P<0.05). In the high eccentricity group, the abduction arm of the affected hip joint was positively correlated with the femoral eccentricity, acetabular eccentricity and joint eccentricity(r=0.633, P<0.001;r=0.384, P=0.005;r=0.690, P<0.001). The same results were also obtained in the healthy side(r=0.688, P<0.001;r=0.574, P<0.001;r=0.765, P<0.001). In the standard eccentricity group, the abduction arm of the affected hip joint was positively correlated with the femoral eccentricity, acetabular eccentricity and combined eccentricity(r=0.734, P<0.001;r=0.418, P<0.001;r=0.749, P<0.001). The same results were also obtained in the healthy side(r=0.775, P<0.001;r=0.397, P<0.001;r=0.773, P<0.001). The difference of the length of both lower limbs was significantly correlated with the difference of bilateral joint eccentricity and bilateral abduction arm (r=0.376, P=0.006;r=-0.346, P=0.012). There was no significant correlation between the difference of the length of both lower limbs and the difference of bilateral joint eccentricity and bilateral abduction arm (r=-0.009, P=0.919;r=-0.036, P=0.682). There was no significant difference in Harris score between two groups at the last follow-up(P>0.05). At the last follow-up, Trendelenburg was negative in all patients in both groups, and the prostheses were stable. CONCLUSION: Both Corail standard stem and high offset stem may be effectively reconstruct the femoral offset, reconstruct the anatomical structure and biomechanics of the hip joint, and maintain the length of lower limbs and the stability of the hip joint in the unilateral primary total hip arthroplasty. Although the offset of the femur was not reconstructed normally in some cases, the stability of the components and postoperative function were not affected.

Early patellar tendon rupture after total knee arthroplasty: A direct repair method.

BACKGROUND: Patellar tendon rupture after total knee arthroplasty (TKA) is a catastrophic complication. Although the occurrence of this injury is rare, it can lead to significant dysfunction for the patient and is very tricky to deal with. There has been no standard treatment for early patella tendon rupture after TKA, and long-term follow-up data are lacking. AIM: To introduce a direct repair method for early patella tendon rupture following TKA and determine the clinical outcomes and complications of this method. METHODS: During the period of 2008 to 2021, 3265 consecutive TKAs were retrospectively reviewed. Twelve patients developed early patellar tendon rupture postoperatively and were treated by a direct repair method. Mean follow-up was 5.7 years. Demographic, operative, and clinical data were collected. The clinical outcomes were assessed using the Western Ontario and McMaster Universities (WOMAC) score, the Hospital for Special Surgery (HSS) score, knee range of motion, extensor lag, and surgical complications. Descriptive statistics and paired t test were employed to analyze the data. RESULTS: For all 12 patients who underwent direct repair for early patellar tendon rupture, 3 patients failed: One (8.3%) for infection and two (17.6%) for re-fracture. The two patients with re-fracture both underwent reoperation to reconstruct the extensor mechanism and the patient with infection underwent revision surgery. The range of motion was 109.2° ± 10.6° preoperatively to 87.9° ± 11° postoperatively, mean extensor lag was 21° at follow-up, and mean WOMAC and HSS scores were 65.8 ± 30.9 and 60.3 ± 21.7 points, respectively. CONCLUSION: This direct repair method of early patellar tendon rupture is not an ideal therapy. It is actually ineffective for the recovery of knee joint function in patients, and is still associated with severe knee extension lag and high complication rates. Compared with the outcomes of other repair methods mentioned in the literature, this direct repair method shows poor clinical outcomes.

Different squatting positions after total knee arthroplasty: A retrospective study.

BACKGROUND: Total knee arthroplasty (TKA) has been shown to improve quality of life and reduce pain. High-flexion activities such as squatting, kneeling, and floor transfers are mainly listed as demanding tasks. Among them, squatting is an important position. AIM: To provide a new squat position classification and evaluate the different squatting positions of a series of patients after primary TKA. METHODS: From May 2018 to October 2019, we retrospectively reviewed 154 video recordings of the squatting-related motions of patients after TKA. Among the included patients, 119 were women and 35 were men. Their mean age at the index surgery was 61.4 years (range, 30 to 77). RESULTS: The median follow-up was 12 mo (range, 6 to 156 mo). We classified those squatting-related motions into three major variations according to squatting depth: Half squat, parallel squat, and deep squat. The angles of hip flexion, knee flexion, and ankle dorsiflexion were measured in the screenshots captured from the videos at the moment of squatting nadir. A total of 26 patients were classified as half squats, 75 as parallel squats, and 53 as deep squats. The angles of hip flexion, knee flexion, and ankle dorsiflexion all differed significantly among the three squatting positions (P < 0.001). In the parallel squat group, the mean knee flexion angle (°) was 116.5 (SD, 8.1; range, 97 to 137). In the deep squat group, the mean knee flexion angle (°) was 132.5 (SD, 9.3; range, 116 to 158). CONCLUSION: Among the three squatting positions, deep squat showed the highest hip, knee, and ankle flexion angles, followed by the parallel squat. With the improvement of squatting ability, the patient's postoperative satisfaction rate was also significantly enhanced. However, the different squatting abilities of the patients cannot be effectively distinguished from the scoring results (P > 0.05). Our squatting position classification offers a pragmatic approach to evaluating patients' squatting ability after TKA.

[Application of high offset Corail femoral stem prosthesis in unilateral primary total hip arthroplasty].

OBJECTIVE: To investigate the application of high offset femoral stem prosthesis in primary total hip arthroplasty. METHODS: From January 2015 to June 2017, 51 patients with unilateral hip diseases who underwent primary total hip arthroplasty with Corail high offset femoral stem prosthesis(KHO type) were selected for retrospective study, including 20 females and 31 males;the age ranged from 21 to 71 years old with an average of(50.8±13.3) years old. The abduction arm, femoral offset, acetabular offset and the length of lower limbs were measured on the positive X-ray film of hip joint after operation. Harris scores before and after operation and related complications were recorded, and the stability of prosthesis was analyzed. RESULTS: The femoral offset, combined offset and abduction arm of the affected side were significantly greater than those of the healthy side(P<0.05). There was no significant difference in acetabular offset between the affected side and the healthy side (P>0.05). The femoral offset of 17 hips (33.3%) was reconstructed normally, of which 15 cases (88.2%) had equal length of both lower limbs. The femoral offset of 34 hips (66.7%) was greater than that of the healthy side, and 34 cases (100%) had equal length of both lower limbs. All 51 patients were followed up for(42.3±7.3) months. The Harris score increased from 38.0±7.6 before operation to 92.1±3.1 at the final follow-up(P<0.001). CONCLUSION: Although the high offset Corail prosthesis can not normally reconstruct the femoral offset in unilateral primary total hip arthroplasty, it does not affect the reconstruction of the length of lower limbs and the stability of the prosthesis.

Research advances on the application of stem cells in sweat gland regeneration / 中华烧伤杂志

Sweat gland is one of the important appendage organs of the skin, which plays an important role in thermoregulation and homeostasis maintenance. Sweat glands are damaged and unable to self-repair after burns, resulting in perspiration disorders eventually. However, current clinical strategies cannot restore the function of the damaged sweat glands effectively. Therefore, it is urgent to seek treatments that can promote the regeneration of sweat glands and restore their normal functions. Stem cells have extensive sources, low immunogenicity, high proliferation capacity, and multi-directional differentiation potential, which have become a focus in the field of regenerative medicine. In recent years, a variety of stem cells have been induced to differentiate into sweat gland-like tissue with certain secretory function, which provides treatment direction for sweat gland regeneration after burns in clinic. This article reviews the recent research advances on the application of stem cells in sweat gland regeneration from the perspectives of the manner by which stem cells transform into sweat gland cells in different environments and their influencing factors.

Ultrasonographic assessment of cardiac function and disease severity in coronary heart disease.

BACKGROUND: Coronary heart disease (CHD) causes many adverse cardiovascular events and poses a threat to the patient's health and quality of life. AIM: To evaluate ultrasonography for evaluation of cardiac function and lesion degree in patients with CHD. METHODS: A total of 106 patients with CHD (study group) and 106 healthy individuals (control group) in our hospital from March 2019 to September 2020 were selected for this study. All subjects were examined by ultrasound, and the mitral orifice's early-to-late diastolic blood flow velocity ratio (E/A), left ventricular end-diastolic volume (LVDd), and left atrial diameter (LAD) were measured. Values were compared between the study group and healthy group, and the correlation between the ultrasonic parameters of patients with different cardiac function grades and the degree of CHD were assessed. In addition, the ultrasonic parameters of patients with different prognoses were compared after a follow-up for 6 mo. RESULTS: E/A (1.46 ± 0.34) of the study group was smaller than that of the control group (1.88 ± 0.44), while LVDd (58.24 ± 5.05 mm) and LAD (43.31 ± 4.38 mm) were larger (48.15 ± 3.93 and 34.94 ± 2.81, respectively; P < 0.05). E/A for patients with grade III disease (1.41 ± 0.43) was smaller and their LVDd (60.04 ± 4.21 mm) and LA (44.16 ± 2.79 mm) were larger than those in patients with grade II disease (1.71 ± 0.48, 52.18 ± 3.67 mm, and 39.68 ± 2.37, respectively; P < 0.05). Patients with grade IV disease had smaller E/A (1.08 ± 0.39) and larger LVDd (66.81 ± 5.39 mm) and LAD (48.81 ± 3.95 mm) than patients with grade II and III disease (P < 0.05). In patients with moderate disease, E/A (1.44 ± 0.41) was smaller and LVDd (59.95 ± 4.14 mm) and LAD (45.15 ± 2.97 mm) were larger than in patients with mild disease (1.69 ± 0.50, 51.97 ± 3.88 and 38.81 ± 2.56 mm, respectively; P < 0.05). In patients with severe disease, E/A (1.13 ± 0.36) was smaller and LVDd (67.70 ± 6.11 mm) and LAD (49.09 ± 4.05 mm) were larger than in patients with moderate disease (P < 0.05). E/A was negatively correlated with cardiac function classification and disease severity, while LVDd and LAD were positively correlated with cardiac function classification and disease severity (P < 0.05). E/A (1.83 ± 0.51) for patients with good prognosis was higher than that for those with poor prognosis (1.39 ± 0.32), while LVDd (49.60 ± 4.39 mm) and LAD (36.13 ± 3.05 mm) were lower (P < 0.05). CONCLUSION: The ultrasonic parameters of patients with CHD are abnormal, and differ significantly in patients with different cardiac function grades, lesion degree, and prognosis.

Factors influencing knee valgus alignment in Crowe type IV hip dysplasia after total hip arthroplasty.

BACKGROUND: Valgus deformity of the knee remains a complaint after total hip arthroplasty (THA) among some patients with Crowe type IV hip dysplasia. We aimed to identify the knee alignment in these patients before and after surgery, and to explore the factors contributing to postoperative knee valgus alignment. MATERIALS AND METHODS: We retrospectively reviewed a series of Crowe type IV patients who received THA between February 2010 and May 2019 in our hospital. The patients' medical data were collected from the hospital information system. On both preoperative and postoperative full limb length standing radiographs, the following parameters were measured: hip-knee-ankle angle (HKA), mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle, anatomical tibiofemoral angle, anatomical lateral distal femoral angle, femoral neck-shaft angle, pelvic obliquity, limb length, height and lateral distance of hip center, and femoral offset. Univariate and multivariate binary logistic regression were used to identify the factors influencing postoperative knee valgus alignment. RESULTS: A total of 64 Crowe type IV patients (87 hips) were included in the study. Overall, HKA improved from 176.54 ± 3.52° preoperatively to 179.45 ± 4.31° at the last follow-up. Those hips were subdivided into non-valgus group (≥ 177.0°, n = 65) and valgus group (< 177.0°, n = 22) according to postoperative HKA. Only postoperative mLDFA was a significant factor in the multivariate regression model. CONCLUSIONS: The postoperative mLDFA is a major factor related to knee valgus alignment after THA, which combines the preoperative anatomy and surgical reconstruction. Other factors previously published were found to have no significance. LEVEL OF EVIDENCE: III.

Influence of GAS5/MicroRNA-223-3p/P2Y12 Axis on Clopidogrel Response in Coronary Artery Disease.

Background Dual antiplatelet therapy based on aspirin and P2Y12 receptor antagonists such as clopidogrel is currently the primary treatment for coronary artery disease (CAD). However, a percentage of patients exhibit clopidogrel resistance, in which genetic factors play vital roles. This study aimed to investigate the roles of GAS5 (growth arrest-specific 5) and its rs55829688 polymorphism in clopidogrel response in patients with CAD. Methods and Results A total of 444 patients with CAD receiving dual antiplatelet therapy from 2017 to 2018 were enrolled to evaluate the effect of GAS5 single nucleotide polymorphism rs55829688 on platelet reactivity index. Platelets from 37 patients of these patients were purified with microbeads to detect GAS5 and microRNA-223-3p (miR-223-3p) expression. Platelet-rich plasma was isolated from another 17 healthy volunteers and 46 newly diagnosed patients with CAD to detect GAS5 and miR-223-3p expression. A dual-luciferase reporter assay was performed to explore the interaction between miR-223-3p and GAS5 or P2Y12 3'-UTR in (human embryonic kidney 293 cell line that expresses a mutant version of the SV40 large T antigen) HEK 293T and (megakaryoblastic cell line derived in 1983 from the bone marrow of a chronic myeloid leukemia patient with megakaryoblastic crisis) MEG-01 cells. Loss-of-function and gain-of-function experiments were performed to reveal the regulation of GAS5 toward P2Y12 via miR-223-3p in MEG-01 cells. We observed that rs55829688 CC homozygotes showed significantly decreased platelet reactivity index than TT homozygotes in CYP2C19 poor metabolizers. Platelet GAS5 expression correlated positively with both platelet reactivity index and P2Y12 mRNA expressions, whereas platelet miR-223-3p expression negatively correlated with platelet reactivity index. Meanwhile, a negative correlation between GAS5 and miR-223-3p expressions was observed in platelets. MiR-223-3p mimic reduced while the miR-223-3p inhibitor increased the expression of GAS5 and P2Y12 in MEG-01 cells. Knockdown of GAS5 by siRNA increased miR-223-3p expression and decreased P2Y12 expression, which could be reversed by the miR-223-3p inhibitor. Meanwhile, overexpression of GAS5 reduced miR-223-3p expression and increased P2Y12 expression, which could be reversed by miR-223-3p mimic. Conclusions GAS5 rs55829688 polymorphism might affect clopidogrel response in patients with CAD with the CYP2C19 poor metabolizer genotypes, and GAS5 regulates P2Y12 expression and clopidogrel response by acting as a competitive endogenous RNA for miR-223-3p.

SRC3 acetylates calmodulin in the mouse brain to regulate synaptic plasticity and fear learning.

Protein acetylation is a reversible posttranslational modification, which is regulated by lysine acetyltransferase (KAT) and lysine deacetyltransferase (KDAC). Although protein acetylation has been shown to regulate synaptic plasticity, this was mainly for histone protein acetylation. The function and regulation of nonhistone protein acetylation in synaptic plasticity and learning remain largely unknown. Calmodulin (CaM), a ubiquitous Ca2+ sensor, plays critical roles in synaptic plasticity such as long-term potentiation (LTP). During LTP induction, activation of NMDA receptor triggers Ca2+ influx, and the Ca2+ binds with CaM and activates calcium/calmodulin-dependent protein kinase IIα (CaMKIIα). In our previous study, we demonstrated that acetylation of CaM was important for synaptic plasticity and fear learning in mice. However, the KAT responsible for CaM acetylation is currently unknown. Here, following an HEK293 cell-based screen of candidate KATs, steroid receptor coactivator 3 (SRC3) is identified as the most active KAT for CaM. We further demonstrate that SRC3 interacts with and acetylates CaM in a Ca2+ and NMDA receptor-dependent manner. We also show that pharmacological inhibition or genetic downregulation of SRC3 impairs CaM acetylation, synaptic plasticity, and contextual fear learning in mice. Moreover, the effects of SRC3 inhibition on synaptic plasticity and fear learning could be rescued by 3KQ-CaM, a mutant form of CaM, which mimics acetylation. Together, these observations demonstrate that SRC3 acetylates CaM and regulates synaptic plasticity and learning in mice.

The Influence of Femoral Proximal Medullary Morphology on Subtrochanteric Osteotomy in Total Hip Arthroplasty for Unilateral High Dislocated Hips.

OBJECTIVE: To evaluate the predictive values of femoral proximal medullary morphology for the use of subtrochanteric osteotomy (STO) in unilateral Crowe IV developmental dysplasia of the hip (DDH). METHODS: Ninety four patients with unilateral Crowe type IV DDH (59 hips in STO group and 35 hips in the non-STO group) between April 2008 and June 2019 were enrolled. All patients underwent THA using the Pinnacle acetabular shell, ceramic liner and femoral head, the S-ROM stem with proximal sleeve. Three parameters on the standard anteroposterior hip radiographs were measured: the widths of medullary canals at 20 mm above the center of lesser trochanter (CLT)，20 mm below the CLT and the isthmus. Canal flare index (CFI), metaphyseal canal flare index (MCFI), diaphyseal canal flare index (DCFI) were calculated. A S-ROM femoral stem was used in all patients during total hip arthroplasty (THA). RESULTS: The CFI and DCFI in the STO group were lower than those in the non-STO group. However, there was no statistical difference in MCFI between the two groups. The receiver operating characteristic (ROC) curves shown that DCFI had the highest area under the curve (AUC), at 0.885. This was followed by the CFI, which had an AUC of 0.847. The AUC of MCFI was 0.579. The optimal threshold for DCFI was 1.44, which lead to a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 0.771, 0.898, 0.869, and 0.818, respectively. For CFI, the optimal threshold was 3.28, resulting in a sensitivity, specificity, PPV, and NPV of 0.829, 0.729, 0.878, and 0.644, respectively. CONCLUSIONS: The DCFI and CFI may be potent indicators in predicting the use of STO in unilateral Crowe IV DDH. The optimal threshold for CFI and DCFI were 3.28 and 1.44 and had good sensitivity and specificity for predicting the use of STO during THA.

False acetabulum is preoperative guidance for Crowe type IV hips on hip reduction without femoral shortening during total hip arthroplasty.

BACKGROUND: We aimed to analyze if the false acetabulum is a good indicator for determining femoral shortening. METHODS: We retrospectively included 102 patients with unilateral Crowe type IV developmental dysplasia who underwent primary total hip arthroplasty from April 2008 to May 2019. Based on the presence of false acetabulum, the 102 hips were further classified Crowe IVA group and Crowe IVB group. Radiographic measurement included the height of greater trochanter (HGT) preoperatively and postoperatively, which reflected the distalisation of greater trochanter (DGT). Harris hip score (HHS), limb length discrepancy (LLD), and complications were collected as clinical evaluation. RESULTS: Sixty hips were classified into Crowe IVA group, and 42 hips were classified into Crowe IVB group. Within Crowe IVA group, the proportion of hips treated with subtrochanteric osteotomy was significantly higher than that in Crowe IVB group (97% vs. 12%) (P < 0.001). The DGT in Crowe IVA group was also greater (67 vs. 32 mm) (P < 0.001). At last follow-up, both two groups obtained excellent clinical scores. There was no significant difference in postoperative LLD between the two groups (P = 0.001). Six dislocations occurred and three patients developed femoral nerve palsy, while all recovered in a year. CONCLUSION: The false acetabulum is a promising and good indicator for determining femoral shortening.

Jumbo cup in hip joint renovation may cause the center of rotation to increase.

BACKGROUND: Utilizing the large jumbo cup in revision total hip arthroplasty is an effective approach to cure many lacunar and segmental peripheral bone defects. However, with the use of the jumbo cup, the center of the hip joint may become elevated relative to the primary acetabulum, and the diameter of the large cup is greater. AIM: To study the height and the significance of the elevation of the hip joint center. METHODS: Eighty-eight patients matched the criteria for this condition and were included in the study. The center height of the hip joint was measured relative to the opposite normal hip joint. The diameter of the jumbo cup was measured and checked according to operation notes, and the diameter of the jumbo cup was measured with a prosthesis label. Then, the horizontal and vertical centers of rotation were measured on the surgical side and opposite side. The average center height of the hip joint on the renovated side and the opposite side and the position of the hip cup relative to the teardrop were compared using a paired t-test. RESULTS: Radiometric analysis showed that the average hip joint center was elevated by 7.6 mm. The rotational center height delta of the renovated hip was 7.6 ± 5.6 mm, and there was an obvious difference between the two groups (P = 0.00). The difference in horizontal distance was 0.5 ± 5.1 mm (-11.5 -14.0 mm), and there was no obvious difference between the two groups (P = 0.38). According to the foreign standard, the rotational center height delta of the renovated hip was 7.5 ± 6.2 mm, and there was a significant difference between the two groups (P = 0.00). There was no obvious difference between the domestic and foreign standards (P > 0.05) between the two groups. CONCLUSION: The application of the jumbo cup elevates the rotational center of the hip joint, but it is feasible and effective to use the jumbo cup.