Discovery of novel 2-substituted-4-(2-fluorophenoxy) pyridine derivatives possessing pyrazolone and triazole moieties as dual c-Met/VEGFR-2 receptor tyrosine kinase inhibitors.

In our efforts to develop novel dual c-Met/VEGFR-2 inhibitors as potential anticancer agents, a series of 2-substituted-4-(2-fluorophenoxy) pyridine derivatives bearing pyrazolone scaffold were designed and synthesized. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2, especially compound 9h, 12b and 12d. Based on the further enzyme assay in vitro, compound 12d was considered as the most promising one, the IC50 values of which were 0.11µM and 0.19µM for c-Met and VEGFR-2, respectively. Further molecular docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, indicating that 12d was a potential compound for cancer therapy deserving further study.

Interaction between a bubble and a metal target for underwater laser propulsion.

Optical beam deflection and high-speed photographic methods are employed to investigate the interaction mechanism between a laser-induced bubble and a metal target for underwater laser propulsion. A preliminary theory is proposed to reveal the step increases of the kinetic energy transferred to the target during the process of increasing the incident laser energy. This theory also helps to explain the increasing coupling efficiency with incident laser energy for underwater laser propulsion.

Design, synthesis and biological evaluation of 4-aminopyrimidine-5-cabaldehyde oximes as dual inhibitors of c-Met and VEGFR-2.

The synergistically collaboration of c-Met/HGF and VEGFR-2/VEGF leads to development of tumor angiogenesis and progression of various human cancers. Therefore, inhibiting both HGF/c-Met and VEGF/VEGFR signaling may provide a novel and effective therapeutic approach for treating patients with abroad spectrum of tumors. Toward this goal, we designed and synthesized a series of derivatives bearing 4-aminopyrimidine-5-cabaldehyde oxime scaffold as potent dual inhibitors of c-Met and VEGFR-2. The cell proliferation assay in vitro demonstrated most target compounds have inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 14i, 18a and 18b. Based on the further enzyme assay in vitro, compound 18a was considered as the most potent one, the IC50s of which were 210nM and 170nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 10 and 18a with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogs. All the results indicate that 18a is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.

Design, synthesis and structure-activity relationship studies of novel phenoxyacetamide-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes.

The free fatty acid receptor 1 (FFA1) has attracted extensive attention as a novel antidiabetic target in the last decade. Several FFA1 agonists reported in the literature have been suffered from relatively high molecular weight and lipophilicity. We have previously reported the FFA1 agonist 1. Based on the common amide structural characteristic of SAR1 and NIH screened compound, we here describe the continued structure-activity exploration to decrease the molecular weight and lipophilicity of the compound 1 series by converting various amide linkers. All of these efforts lead to the discovery of the preferable lead compound 18, a compound with considerable agonistic activity, high LE and LLE values, lower lipophilicity than previously reported agonists, and appreciable efficacy on glucose tolerance in both normal and type 2 diabetic mice.

Synthesis and biological evaluation of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists.

Free fatty acid receptor 1 (FFA1) is a new potential drug target for the treatment of type 2 diabetes because of its role in amplifying glucose-stimulated insulin secretion in pancreatic ß-cell. In the present studies, we identified phenoxyacetic acid derivative (18b) as a potent FFA1 agonist (EC50=62.3 nM) based on the structure of phenylpropanoic acid derivative 4p. Moreover, compound 18b could significantly improve oral glucose tolerance in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice without observation of hypoglycemic side effect. Additionally, compound 18b exhibited acceptable PK profiles. In summary, compound 18b with ideal PK profiles exhibited good activity in vitro and in vivo, and might be a promising drug candidate for the treatment of diabetes mellitus.

Study of underwater laser propulsion using different target materials.

In order to investigate the influence of target materials, including aluminum (Al), titanium (Ti) and copper (Cu), on underwater laser propulsion, the analytical formula of the target momentum IT is deduced from the enhanced coupling theory of laser propulsion in atmosphere with transparent overlay metal target. The high-speed photography method and numerical simulation are employed to verify the IT model. It is shown that the enhanced coupling theory, which was developed originally for laser propulsion in atmosphere, is also applicable to underwater laser propulsion with metal targets.

Neuronal lack of PDE7a disrupted working memory, spatial learning, and memory but facilitated cued fear memory in mice.

BACKGROUND: PDEs regulate cAMP levels which is critical for PKA activity-dependent activation of CREB-mediated transcription in learning and memory. Inhibitors of PDEs like PDE4 and Pde7 improve learning and memory in rodents. However, the role of PDE7 in cognition or learning and memory has not been reported yet. METHODS: Therefore, we aimed to explore the cognitive effects of a PDE7 subtype, PDE7a, using combined pharmacological and genetic approaches. RESULTS: PDE7a-nko mice showed deficient working memory, impaired novel object recognition, deficient spatial learning & memory, and contextual fear memory, contrary to enhanced cued fear memory, highlighting the potential opposite role of PDE7a in the hippocampal neurons. Further, pharmacological inhibition of PDE7 by AGF2.20 selectively strengthens cued fear memory in C57BL/6 J mice, decreasing its extinction but did not affect cognitive processes assessed in other behavioral tests. The further biochemical analysis detected deficient cAMP in neural cell culture with genetic excision of the PDE7a gene, as well as in the hippocampus of PDE7a-nko mice in vivo. Importantly, we found overexpression of PKA-R and the reduced level of pPKA-C in the hippocampus of PDE7a-nko mice, suggesting a novel mechanism of the cAMP regulation by PDE7a. Consequently, the decreased phosphorylation of CREB, CAMKII, eif2a, ERK, and AMPK, and reduced total level of NR2A have been found in the brain of PDE7a-nko animals. Notably, genetic excision of PDE7a in neurons was not able to change the expression of NR2B, BDNF, synapsin1, synaptophysin, or snap25. CONCLUSION: Altogether, our current findings demonstrated, for the first time, the role of PDE7a in cognitive processes. Future studies will untangle PDE7a-dependent neurobiological and molecular-cellular mechanisms related to cAMP-associated disorders.

The Responses of Light Reaction of Photosynthesis to Dynamic Sunflecks in a Typically Shade-Tolerant Species Panax notoginseng.

Light is highly heterogeneous in natural conditions, and plants need to evolve a series of strategies to acclimate the dynamic light since it is immobile. The present study aimed to elucidate the response of light reaction of photosynthesis to dynamic sunflecks in a shade-tolerant species Panax notoginseng and to examine the regulatory mechanisms involved in an adaptation to the simulated sunflecks. When P. notoginseng was exposed to the simulated sunflecks, non-photochemical quenching (NPQ) increased rapidly to the maximum value. Moreover, in response to the simulated sunflecks, there was a rapid increase in light-dependent heat dissipation quantum efficiency of photosystem II (PSII) (ΦNPQ), while the maximum quantum yield of PSII under light (F v'/F m') declined. The relatively high fluorescence and constitutive heat dissipation quantum efficiency of PSII (Φf,d) in the plants exposed to transient high light (400, 800, and 1,600 µmol m-2 s-1) was accompanied by the low effective photochemical quantum yield of PSII (ΦPSII) after the dark recovery for 15 min, whereas the plants exposed to transient low light (50 µmol m-2 s-1) has been shown to lead to significant elevation in ΦPSII after darkness recovery. Furthermore, PSII fluorescence and constitutive heat dissipation electron transfer rate (J f,d) was increased with the intensity of the simulated sunflecks, the residual absorbed energy used for the non-net carboxylative processes (J NC) was decreased when the response of electron transfer rate of NPQ pathway of PSII (J NPQ) to transient low light is restricted. In addition, the acceptor-side limitation of PSI [Y(NA)] was increased, while the donor-side limitation of photosystems I (PSI) [Y(ND)] was decreased at transient high light conditions accompanied with active cyclic electron flow (CEF). Meanwhile, when the leaves were exposed to transient high light, the xanthophyll cycle (V cycle) was activated and subsequently, the J NPQ began to increase. The de-epoxidation state [(Z + A)/(V + A + Z)] was strongly correlated with NPQ in response to the sunflecks. In the present study, a rapid engagement of lutein epoxide (Lx) after the low intensity of sunfleck together with the lower NPQ contributed to an elevation in the maximum photochemical quantum efficiency of PSII under the light. The analysis based on the correlation between the CEF and electron flow devoted to Ribulose-1, 5-bisphosphate (RuBP) oxygenation (J O) indicated that at a high light intensity of sunflecks, the electron flow largely devoted to RuBP oxygenation would contribute to the operation of the CEF. Overall, photorespiration plays an important role in regulating the CEF of the shade-tolerant species, such as P. notoginseng in response to transient high light, whereas active Lx cycle together with the decelerated NPQ may be an effective mechanism of elevating the maximum photochemical quantum efficiency of PSII under light exposure to transient low light.

Nanosecond shock wave-induced surface acoustic waves and dynamic fracture at fluid-solid boundaries.

We investigate the generation and propagation characteristics of leaky Rayleigh waves (LRWs) caused by a spherical shock wave incident on a water-glass boundary both experimentally and numerically. The maximum tensile stress produced on the solid boundary is attributed to the dynamic interaction between the LRWs and an evanescent wave generated concomitantly along the boundary. The resultant tensile stress field drives the initiation of crack formation from pre-existing surface flaws and their subsequent extension along a circular trajectory, confirmative with the direction of the principal stress on the boundary. We further demonstrate that this unique ringlike fracture pattern, prevalent in damage produced by high-speed impact, can be best described by the Tuler-Butcher criterion for dynamic failure in brittle materials. The orientation of the ring fracture extension into the solid also follows closely with the trajectory of the local maximum tensile stress distribution.

Construction of a species-specific vector for improved plastid transformation efficiency in Capsicum annuum L.

In the present study, we focused on designing a species-specific chloroplast vector for Capsicum annuum L. and finding out its transformation efficiency compared to a heterologous vector. The plastid transformation vector (CaIA) was designed to target homologous regions trnA and trnI of IR region. A selectable marker gene aadA, whose expression is controlled by psbA promoter and terminator, was cloned between two flanking regions. A heterologous vector pRB95, which targets trnfM and trnG of LSC region along with aadA driven by rrn promoter and psbA terminator, was also used for developing plastid transformation in Capsicum. Cotyledonary explants were bombarded with stabilized biolistic parameters: 900 psi pressure and 9 cm flight distance, and optimized regeneration protocol (0.7 mg/L TDZ + 0.2 mg/L IAA) was used to obtain transplastomic lines on selection medium (300 mg/L spectinomycin). The aadA integration and homoplasmy were confirmed by obtaining 1.2 and 3.7 kb amplicons in CaIA transformants and subsequently verified by Southern blotting, whereas in pRB95 transformants, integration was confirmed by PCR with 1.45 kb and 255 bp amplicons corresponding to aadA integration and flanks, respectively. The transformation efficiencies attained with two plastid vectors were found to be 20%, i.e., 10 transplastomic lines in 50 bombarded plates, with CaIA and 2%, i.e., 1 transplastomic line in 50 bombarded plates, with heterologous pRB95, respectively.

Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2.

c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 ±â€¯0.1 nM and 5.0 ±â€¯0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 ±â€¯0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 ±â€¯0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study.

Application of holographic image technology in intracranial tumor surgery / 肿瘤研究与临床

Objective:To explore the feasibility and clinical value of holographic image technology in intracranial tumor surgery.Methods:A total of 40 patients with intracranial tumors in Beijing Tiantan Hospital, Capital Medical University from November 2020 to March 2021 were randomly divided into the experimental group (20 cases) and the control group (20 cases) based on the random number table. Patients in the experimental group underwent craniotomy assisted by holographic technology, while patients in the control group underwent conventional craniotomy. The Karnofsky performance status scores of patients before the operation and 7 days after the operation were recorded, and the self-rating anxiety scale was applied to evaluate the anxiety of the patients' families.Results:The head CT 12 h after surgery showed no tumor cavity hyperdensity in all patients. The head magnetic resonance imaging (MRI) 72 h after surgery revealed 17 cases of total resection and 3 cases of subtotal resection in the experimental group; in the control group, there were 16 cases of total resection and 4 cases of subtotal resection. In the experimental group, 1 patient's left lower limb muscle strength was grade Ⅱ after the operation and recovered to grade Ⅴ-at discharge. In the control group, the left limb muscle strength of 2 patients was grade Ⅲ after the operation and recovered to grade Ⅴ at discharge. The patients with Karnofsky scores of 60, 70, 80, 90, 100 scores were found in 1 case, 5 cases, 8 cases, 6 cases, 0, respectively of the experimental group and 0, 4 cases, 9 cases, 6 cases, 1 case, respectively of the control group before the operation, and the difference was statistically significant ( P > 0.05); the patients with Karnofsky scores of 50, 60, 70, 80, 90, 100 scores were found in 1 case, 0, 0, 7 cases, 9 cases,3 cases, respectively of the experimental group and 0, 3 cases, 6 cases, 4 cases, 5 cases, 2 cases, respectively of the control group after the operation, and the difference was statistically significant ( P = 0.018). The difference of Karnofsky score before and after the operation in the experimental group was statistically significant ( P = 0.029), while there was no statistically significant difference in the Karnofsky score before and after the operation in the control group ( P = 0.241). There were 8 cases, 9 cases, 2 cases and 1 case of non-anxiety, mild anxiety, moderate anxiety, severe anxiety, respectively in the experimental group and 3 cases, 4 cases, 8 cases and 4 cases of non-anxiety, mild anxiety, moderate anxiety, severe anxiety, respectively in the control group before the operation; there were 9 cases, 9 cases, 2 cases and 0 case of non-anxiety, mild anxiety, moderate anxiety, severe anxiety, respectively in the experimental group and 2 cases, 5 cases, 9 cases and 4 cases of non-anxiety, mild anxiety, moderate anxiety, severe anxiety, respectively in the control group after the operation. The preoperative and postoperative anxiety scores of the experimental group were all lower than those of the control group, and the differences were statistically significant (preoperative P = 0.016,postoperative P = 0.002). Conclusions:Holographic technology can assist in formulating an accurate surgical plan before intracranial tumor surgery, intuitively display the anatomical relationship between the tumor and its surrounding important tissues during operation, reduce the surgical side injuries and decrease the anxiety of the patients' family.

Discussion on the use of occupational contraindication cardiovascular disease in Technical Specifications for Occupational Health Surveillance (GBZ 188-2014) / 中华劳动卫生职业病杂志

Technical Specifications for Occupational Health Surveillance (GBZ 188-2014) has played an important role in screening occupational contraindications and preventing occupational diseases since its implementation. However, during the use of occupational health examination, we found that the use of occupational contraindication on cardiovascular disease was not "homogenized" due to the differences in the understanding of various physical examination institutions. Therefore, this paper mainly discussed the connotation and quantitative standards of organic heart disease, arrhythmia, hypertension in the occupational contraindication cardiovascular disease in the specification for "homogenization".

Advances in tumor regression patterns and safe distance of distal resection margin after neoadjuvant therapy for rectal cancer / 中华胃肠外科杂志

Neoadjuvant therapy has been widely applied in the treatment of rectal cancer, which can shrink tumor size, lower tumor staging and improve the prognosis. It has been the standard preoperative treatment for patients with locally advanced rectal cancer. The efficacy of neoadjuvant therapy for rectal cancer patients varies between individuals, and the results of tumor regression are obviously different. Some patients with good tumor regression even achieve pathological complete response (pCR). Tumor regression is of great significance for the selection of surgical regimes and the determination of distal resection margin. However, few studies focus on tumor regression patterns. Controversies on the safe distance of distal resection margin after neoadjuvant treatment still exist. Therefore, based on the current research progress, this review summarized the main tumor regression patterns after neoadjuvant therapy for rectal cancer, and classified them into three types: tumor shrinkage, tumor fragmentation, and mucin pool formation. And macroscopic regression and microscopic regression of tumors were compared to describe the phenomenon of non-synchronous regression. Then, the safety of non-surgical treatment for patients with clinical complete response (cCR) was analyzed to elaborate the necessity of surgical treatment. Finally, the review studied the safe surgical resection range to explore the safe distance of distal resection margin.

The impact of extended waiting time on tumor regression after neoadjuvant chemoradiotherapy for locally advanced rectal cancer / 中华外科杂志

Objective: To investigate the influence of extending the waiting time on tumor regression after neoadjuvant chemoradiology (nCRT) in patients with locally advanced rectal cancer (LARC). Methods: Clinicopathological data from 728 LARC patients who completed nCRT treatment at the First Affiliated Hospital, Naval Medical University from January 2012 to December 2021 were collected for retrospective analysis. The primary research endpoint was the sustained complete response (SCR). There were 498 males and 230 females, with an age (M(IQR)) of 58 (15) years (range: 22 to 89 years). Logistic regression models were used to explore whether waiting time was an independent factor affecting SCR. Curve fitting was used to represent the relationship between the cumulative occurrence rate of SCR and the waiting time. The patients were divided into a conventional waiting time group (4 to <12 weeks, n=581) and an extended waiting time group (12 to<20 weeks, n=147). Comparisons regarding tumor regression, organ preservation, and surgical conditions between the two groups were made using the t test, Wilcoxon rank sum test, or χ2 test as appropriate. The Log-rank test was used to elucidate the survival discrepancies between the two groups. Results: The SCR rate of all patients was 21.6% (157/728). The waiting time was an independent influencing factor for SCR, with each additional day corresponding to an OR value of 1.010 (95%CI: 1.001 to 1.020, P=0.031). The cumulative rate of SCR occurrence gradually increased with the extension of waiting time, with the fastest increase between the 9th to <10th week. The SCR rate in the extended waiting time group was higher (27.9%(41/147) vs. 20.0%(116/581), χ2=3.901, P=0.048), and the organ preservation rate during the follow-up period was higher (21.1%(31/147) vs. 10.7%(62/581), χ2=10.510, P=0.001). The 3-year local recurrence/regrowth-free survival rates were 94.0% and 91.1%, the 3-year disease-free survival rates were 76.6% and 75.4%, and the 3-year overall survival rates were 95.6% and 92.2% for the conventional and extended waiting time groups, respectively, with no statistical differences in local recurrence/regrowth-free survival, disease-free survival and overall survival between the two groups (χ2=1.878, P=0.171; χ2=0.078, P=0.780; χ2=1.265, P=0.261). Conclusions: An extended waiting time is conducive to tumor regression, and extending the waiting time to 12 to <20 weeks after nCRT can improve the SCR rate and organ preservation rate, without increasing the difficulty of surgery or altering the oncological outcomes of patients.

A novel mitochondria-targeting fluorescent probe for hydrogen sulfide in living cells.

A novel mitochondria-targeting fluorescent probe compound S-N3 for hydrogen sulfide (H2 S) in living cells has been designed and synthesized in this study. This article contained the chemosynthesis and some studies on bioactivity of the target compound in living cells. Compound S-N3 is easy to synthesize and can remain stable under the effect of pH, system and photostability. In addition, it shows low cytotoxicity in cell imaging. And it can react with H2 S highly selective in PBS or FBS solution, which would cause the obvious increase in fluorescence intensity. Therefore, the low-cost detection method for H2 S is allowed for monitoring the quantity of H2 S existed in the mitochondria.

A haplotype in CFH family genes confers high risk of rare glomerular nephropathies.

Despite distinct renal lesions, a series of rare glomerular nephropathies are reportedly mediated by complement overactivation. Genetic variations in complement genes contribute to disease risk, but the relationship of genotype to phenotype has not been straightforward. Here, we screened 11 complement genes from 91 patients with atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G) and membranoproliferative glomerulonephritis type I (MPGN I), and identified the concomitant presence of three missense variations located within the human complement Factor H (CFH) gene cluster. The three variations, rs55807605, rs61737525 and rs57960694, have strong linkage disequilibrium; subsequent haplotype analysis indicated that ATA increased the susceptibility of these renal diseases. In silico analysis, the CFHR3 rs61737525-T risk allele altered the physical and structural properties and generated a reduction in binding affinity of the CFHR3/C3b complex. Surface plasmon resonance (SPR) binding analysis further demonstrated the substitution induced a decrease of two orders of magnitude in C3b-binding properties, with a declined cofactor activity in fluid phase. These data suggest that the haplotype carrying the causative allele behaves as a partial C3 convertase deficiency, predisposing individuals to diverse pathologic lesions underlying complement overactivation. Such genotype-phenotype discrepancies allow better understanding about these nephropathies mediated by genetic complement disorders.

Design, Synthesis, and Pharmacological Characterization of N-(4-(2 (6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)yl)ethyl)phenyl)quinazolin-4-amine Derivatives: Novel Inhibitors Reversing P-Glycoprotein-Mediated Multidrug Resistance.

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a principal obstacle for successful cancer chemotherapy. A novel P-gp inhibitor with a quinazoline scaffold, 12k, was considered to be the most promising for in-depth study. 12k possessed high potency (EC50 = 57.9 ± 3.5 nM), low cytotoxicity, and long duration of activity in reversing doxorubicin (DOX) resistance in K562/A02 cells. 12k also boosted the potency of other MDR-related cytotoxic agents with different structures, increased accumulation of DOX, blocked P-gp-mediated Rh123 efflux, and suppressed P-gp ATPase activity in K562/A02 MDR cells. However, 12k did not have any effects on CYP3A4 activity or P-gp expression. In particular, 12k had a good half-life and oral bioavailability and displayed no influence on DOX metabolism to obviate the side effects closely related to increased plasma concentrations of cytotoxic agents in vivo.

Case report of habitual dislocation of the hip in children and a review of systematic literature / 中华骨科杂志

Objective:To explore the clinical effect of observation and psychological intervention, splint or brace fixation as well as surgical treatment on habitual dislocation of the hip (HDH) and to combine the authors' data with a compilation of the cases from the literature, evaluingating the epidemiological characteristics of HDH and the treatment scheme to maintain the stability of hip joint by systematic literature review in children.Methods:A retrospective analysis of the relevant data of 11 patients (12 hips) with HDH were treated from March 2007 to March 2021, including 2 boys and 9 girls. The age of the first dislocation was 2.25 (1.66, 3.75) years old and 4.33 (3.33, 6.17) years old at the age of diagnosis. At the same time, the relevant literature reports were searched from 1932 to 2022, and 24 HDH patients reports and clinical studies were confirmed to be included in this study according to the inclusion and exclusion criteria. The data of 33 patients (38 hips) with HDH who were obtained in the literature, including 5 boys and 28 girls. The age of the first dislocation was 2.00 (1.50, 2.00) years old and 4.00 (2.55, 5.00) years old at the age of diagnosis. A total of 44 patients (50 hips) with HDH who were analyzed, including gender, age of first dislocation, age of diagnosis, mode of stimulating dislocation, side and direction of dislocation, accompanying symptoms, family history, trauma history and imaging examination. The data of 41 patients with HDH (3 patients were excluded due to lack of treatment description) were treated with observation and psychological intervention in 19 patients, splint or brace fixation in 13 patients, and surgical treatment in 9 patients. The femoral neck-stem angle, acetabular index, central edge angle (CE angle) and Reimers instability index were measured by AutoCAD software, and the hip function was evaluated by Harris standard. Meantime, the disappearance time of dislocation was recorded.Results:The average follow-up time of 44 patients (50 hips) with HDH were 4.05±2.93 years old, and the time of disappearance of dislocation after treatment were 1.28±1.19 years old. Patients were diagnosed as 7 boys and 37 girls, 30 right and 8 left as well as 6 bilateral, the age of the first dislocation was 2.64±1.54 years old and 4.52±2.64 years old at the age of diagnosis. The data of 39 patients took hip flexion, adduction, internal rotation or hip flexion and adduction as the mode of stimulating dislocation. There were 43 patients with posterior dislocation, 41 patients with an audible "click" sound during dislocation, 36 patients with painless dislocation, and 37 patients with "vacuum phenomenon" were captured at the moment of dislocation. All patients with HDH had no specific family history and obvious history of trauma. There was no significant difference in general data between observation and psychological intervention group, splint or brace fixation group as well as surgical treatment group ( P>0.05). Harris standard to evaluate hip function, CE angle and Reimers instability index of the affected side were significantly different from those before and after treatment at the moment of dislocation ( H=127.51, P<0.001; H=55.70, P<0.001; H=54.69, P<0.001). Compared with the immediate disappearance of dislocation in the surgical treatment group, the disappearance time of dislocation in the observation and psychological intervention group and the splint or brace fixation group were significantly longer, and the difference was statistically significant ( H=20.83, P<0.001). Conclusion:Without specific family history and obvious trauma at young girls, painless posterior dislocation of hip with an audible "click" sound and "vacuum phenomenon" at the moment of dislocation are the significant epidemiological characteristics of HDH. Observation and psychological intervention, splint or brace fixation are recommended as the initial treatment scheme. When conservative treatment is ineffective, surgical treatment is needed to stabilize the hip joint quickly.

Systems pharmacology dissection of action mechanisms for herbs in osteoporosis treatment / 中草药·英文版

Objective: Osteoporosis has become the biggest cause of non-fatal health issue. Currently, the limitations of traditional anti-osteoporosis drugs such as long-term ill-effects and drug resistance, have raised concerns toward complementary and alternative therapies, particularly herbal medicines and their natural active compounds. Thus, this study aimed to provide an integrative analysis of active chemicals, drug targets and interacting pathways of the herbs for osteoporosis treatment. Methods: Here, we introduced a systematic pharmacology model, combining the absorption, distribution, metabolism, and excretion (ADME) screening model, drug targeting and network pharmacology, to probe into the therapeutic mechanisms of herbs in osteoporosis. Results: We obtained 86 natural compounds with favorable pharmacokinetic profiles and their 58 targets from seven osteoporosis-related herbs. Network analysis revealed that they probably synergistically work through multiple mechanisms, such as suppressing inflammatory response, maintaining bone metabolism or improving organism immunity, to benefit patients with osteoporosis. Furthermore, experimental results showed that all the five compounds (calycosin, asperosaponin VI, hederagenin, betulinic acid and luteolin) enhanced osteoblast proliferation and differentiation in vitro, which corroborated the validity of this system pharmacology approach. Notably, gentisin and aureusidin among the identified compounds were first predicted to be associated with osteoporosis. Conclusion: Herbs and their natural compounds, being characterized as the classical combination therapies, might be engaged in multiple mechanisms to coordinately improve the osteoporosis symptoms. This work may contribute to offer novel strategies and clues for the therapy and drug discovery of osteoporosis and other complex diseases.