OBJECTIVE To prepare berberine/piperine co-loaded self-microemulsion drug delivery system （BBR/PIP- SMEDDS）， evaluate its physicochemical properties， in vitro release and pharmacokinetic characteristics. METHODS The drug loading mass ratio of berberine （BBR） and piperine （PIP） in the preparation was determined by the everted intestinal sac method. The oil-phase， emulsifier and co-emulsifier were determined by solubility detection， compatibility evaluation and pseudo-ternary phase diagram， respectively. The formulation of blank self-microemulsion drug delivery system （SMEDDS） was optimized and verified by central composite design-response surface methodology with the amount of oil-phase and the mass ratio of emulsifier to co-emulsifier as factors， and the comprehensive score of particle size and Zeta potential as response value. According to the optimal prescription， BBR/PIP-SMEDDS was prepared by adding excessive BBR and PIP raw materials under magnetic stirring， and its physicochemical properties， in vitro release behavior and pharmacokinetic characteristics in rats were investigated. RESULTS The drug loading mass ratio of BBR and PIP was 1∶1. The optimal prescription included oil-phase （ethyl oleate） accounted for 18.54%， emulsifier （Tween-80） accounted for 52.16%， and co-emulsifier （polyethylene glycol 400） accounted for 29.30%. Three verification experiments showed that the average particle size of blank SMEDDS was （16.49±0.49） nm； the Zeta potential was （－16.22±0.77） mV； the comprehensive score was 0.97， the relative deviation of which from the predicted value （0.95） was 2.11%. The prepared BBR/PIP-SMEDDS was an oil-in-water microemulsion， which was a golden yellow oily liquid with a spherical shape. The average particle size was （32.90±0.38） nm， and the Zeta potential was （－19.17±0.70） mV. The encapsulation efficiency of BBR was （90.44±0.88）% ， and the drug loading was （10.18±0.17） mg/g. The encapsulation efficiency of PIP was （87.48±1.13）%， and the drug loading was （9.41±0.17） mg/g. BBR/PIP-SMEDDS had good stability at low temperature （4 ℃ ） in the dark， centri-fugation and dilution. The results of in vitro release showed that the cumulative release percentage of BBR in simulated intestinal fluid for 24 h was significantly higher than that of the raw drug after the preparation of SMEDDS. The pharmacokinetic results in rats showed that the peak concentration and area under the drug- concentration time curve （AUC0－）t of BBR/PIP-SMEDDS were 4.61 and 7.07 times higher than those of the raw drug respectively， and the relative bioavailability was 707.484%. CONCLUSIONS BBR/PIP-SMEDDS is successfully prepared， and the in vitro release and bioavailability of the preparation are greatly improved compared with the raw material.

Objective:To explore the genetic basis of eighteen patients with tetrahydrobiopterin deficiency (BH4D) from Gansu Province.Methods:Eighteen patients diagnosed with BH4D at Gansu Provincial Maternal and Child Health Care Hospital from January 2018 to December 2021 were selected as the study subjects. Whole exome sequencing was carried out, and candidate variants were verified by Sanger sequencing.Results:All of the thirty-six alleles of the eighteen patients were successfully determined by molecular genetic testing. Sixteen patients were found to harbor variants of the PTS gene, and two had harbored variants of the QDPR gene. Ten variants were detected in the PTS gene, with the most common ones being c. 259C>T (34.38%) and c. 286G>A (15.63%). Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c. 259C>T was classified as a pathogenic variant, whilst the c. 286G>A, c. 166G>A, c. 200C>T, c. 272A>G, c. 402A>C, c. 421G>T, c. 84-291A>G and c. 317C>T were classified as likely pathogenic variants. A novel c. 289_290insCTT variant was classified as likely pathogenic (PM1+ PM2_Supporting+ PM3+ PP3+ PP4). The two variants (c.478C>T and c. 665C>T) detected in the QDPR gene were both classified as variants of uncertain significance (PM1+ PM2_Supporting+ PP3+ PP4). Conclusion:Genetic testing has clarified the pathogenic variants in these BH4D patients, which has enabled timely and accurate clinical intervention and treatment, and provided a reference for genetic counseling and reproductive guidance for their families.

Objective To explore the correlation between serum fibroblast growth factor-23 (FGF23) concentration and heart failure and all-cause death in patients with end-stage renal disease (ESRD).Methods The prospective cohort study design was used in the present study.The ESRD patients who were admitted to the department of ne-phropathy in the Hospital and without heart failure symptoms were recruited in this study.The data of patients was collected through baseline questionnaires, physical examinations, echocardiography, and laboratory examinations.The serum FGF23 levels were measured by enzyme-linked immunosorbent assay (ELISA) .The follow-up time was 2 years.The onset of heart failure (ACC/AHA stage C-D) and all-cause death were composite endpoint events.The Cox proportional risk model was used to explore the risk factors of outcome events.Through subgroup analyses and interaction analyses, further exploration was conducted to determine whether there was heterogeneity in the as-sociation between FGF23 and outcome events in different subgroups.Results Ultimately,107 ESRD patients were included in this study, with an average age of (52.00 ± 12.51) years.There were 39 males (36.45％), and the median follow-up time was 23 months (21, 25 months).There were 32 (29.9％) outcome events, of which 22 (20.6％) onset of heart failure and 10 (9.3％) all-cause of deaths.The results of this study showed that the con-centration of FGF23 in the outcome event group was significantly higher than that in the non-event group [ (4.40 ± 1.16) pmol/ml vs (3.85 ± 0.82) pmol/ml,P<0.05].The Cox proportional risk model showed that the elevated FGF23 was associated with increased risk of the composite endpoint events in ESRD patients (HR=1.730 , 95％CI:1.164-2.570 , P=0.007) .Subgroup analyses showed that there was an interactive effect between FGF23 levels and gender on the risk of cardiovascular outcome events.Especially in male ESRD patients, the increased FGF23 level was correlated with a higher risk of cardiovascular events (P-interaction <0.05).Conclusion Elevated serum FGF23 is an independent risk factor for the onset of heart failure and all-cause of mortality in ESRD patients, especially in male patients.

Osteonecrosis of the femoral head (ONFH) is one of the common and difficult-to-treat orthopedic diseases caused by a variety of factors that lead to abnormal blood flow to the femoral head, which in turn leads to deformation and collapse of the femoral head and eventually results in severe hip joint dysfunction. The key to the treatment is early diagnosis and correct treatment according to the stage classification and active prevention of further aggravation of ONFH aiming to delay or avoid hip replacement surgery in young and middle-aged patients. At present, there are various non-surgical and surgical hip-preserving modalities for early ONFH, designed to slow down the progression of the disease, prevent the femoral head from collapsing and stop the mild collapse. In recent years, with the emergence and development of bone reconstruction biomaterials, artificial bone reconstruction after scraping of ONFH lesions has shown great potential in the treatment of early ONFH. The authors review the research progress in hip-preserving modalities for early ONFH in young and middle-aged patients from non-surgical and surgical perspectives, hoping to provide a reference for clinical treatment of early ONFH.

Mucinous adenocarcinoma of the prostate is a rare pathological type of prostate cancer. We reported one case. The patient went to see a doctor because of intermittent hematuria. He was diagnosed as prostate adenocarcinoma before operation. He underwent laparoscopic radical prostatectomy. Postoperative pathological examination showed mucinous adenocarcinoma of the prostate. The patient was followed up for six months. Imaging showed no signs of recurrence and metastasis with normal tPSA.

Objective:Exploring effective methods of information management in the practice of constructing practical and beautiful websites.Methods:Building a website that fits the management concept through research needs, page planning and design, column layout and other links. Standardize the website management by improving the management system, improving the management mechanism, and building a solid foundation for information security protection.Results:The revised website becomes not only an important window and bridge for external publicity and communication of the scientific research institutes, but also a concentrated embodiment of the achievements of information construction and management quality.Conclusions:Unified construction and management of the website can integrate resources, realize the coordination and efficiency of scientific research management, significantly improve the timeliness of information dissemination, promote the diversification of publicity modes, and improve the quality of scientific research services.

Objective:To perform a prospective cohort study to identify individual susceptibility of glucocorticoid (GC) -associated osteonecrosis of the femoral head (GA-ONFH) and their clinical and genetic risk factors. Methods:The present prospective cohort study enrolled patients who received their first GC therapy between July 2015 and January 2018 at Zhongshan Hospital. All patients did not receive any GC treatment before enrollment. Further, they planned to start GC treatment with the dose (equivalent prednisone) of ≥30 mg/d, lasted ≥3 weeks, or pulse dose ≥200 mg/d, lasted ≥3 d. Blood samples were collected before GC treatment to evaluate bone metabolism and its released factors. Hip MRI was performed at the 1st, 3rd, 6th, 12th and 24th month to diagnose GA-ONFH. All patients were followed-up for ≥2 years. The endpoint was regarded as diagnosis of GA-ONFH or completion of 2 years follow-up. Lasso regression was performed to determine which clinical features were associated with GA-ONFH. A nested case-control sub-cohort (A, n=12) was established prospectively based on the main cohort by 1∶1 matching. Whole exome sequencing was performed to screen differential and functional candidate single nucleotide polymorphisms and insertion-deletions (SNP/InDels). Another sub-cohort (B, n=50) was constructed retrospectively in patients with GA-ONFH and non-ONFH patients received standard high dose GC treatment for more than two years. The candidate SNP/InDels were verified by Sanger sequencing based on the patients from sub-cohort B. Results:A total of 96 patients were enrolled of which 88 of them (32 males and 56 females, mean age 42.30 years) completed follow-up. Eight cases (9.1%) were diagnosed with GA-ONFH. The median time from the start of GC therapy to the diagnosis of ONFH was 53.00(34.00,13.50) days. The baseline characteristics, such as age, sex and body mass index, indicated no significant difference between the ONFH group and the non-ONFH group. The cumulative GC dose of the ONFH patients in the first month was higher than that of non-ONFH [32.74(29.55, 47.05) mg/kg vs. 24.00(21.10, 29.45) mg/kg, Z=-2.410, P=0.016]. However, there was no significant difference of patients who underwent pulse therapy (37.5% vs. 10.0%, adjusted χ 2=2.829, P=0.093). The ratio of serum apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) in patients with ONFH was higher than that in non-ONFH group before GC use [0.95(0.80, 1.50) vs. 0.70(0.60, 0.80), Z=-2.875, P=0.000]. Due to the multicollinearity, Lasso regression model was performed to reduce overfitting. All variables were included in the model. The results suggested that higher ApoB/ApoA1 ratio, lower serum β-c-terminal telopeptide (β-CTX) and higher cumulative GC dose in the first month were the top three risk factors of GA-ONFH. This model had an accuracy of 0.982 in internal validation. Seven differential candidate SNP/InDels were found by whole exome sequencing of sub-cohort A. We further verified these SNP/InDels in sub-cohort B. The patients with COLEC12 mutation (rs2305027, G1816A) were at risk of GA-ONFH ( OR=6.00, 95% CI: 1.17, 30.73). Conclusion:Higher first-month GC dose, lower serum β-CTX level before treatment, higher ApoB/ApoA1 ratio and COLEC12 mutation (rs2305027, G1816A) could increase the risk of GA-ONFH.

Pancreatic cancer stroma plays a critical role in tumor progression, invasion, metastasis and resistance.Targeting tumor cell alone could not meet the demand for prolonging patients'' survival.Growing studies have laid emphasis on developing combined regimens between targeting pancreatic cancer stroma and chemotherapy, radiotherapy and immunotherapy.We are faced with some new opportunities in spite of the great challenges brought to the research and development of targeting drugs owing to the complicated stroma components, crosstalking signal pathways and abnormal angiogenesis of pancreatic cancer.In this article, recent advances in therapeutic strategies of targeting pancreatic cancer stroma are reviewed and analyzed from the aspects of extracellular matrix (ECM), cancer associated fibroblasts (CAFs) and vessels, in the hope of providing some novel ideas for targeting therapy against pancreatic cancer.

The jaw and femur are commonly used sites in basic research for modeling bone defects or inserting implants. An increasing number of studies have identified that the jaw and femur indeed show great differences in embryonic development and growth, histomorphology and bone metabolism. A literature review showed that, compared with the femur, the main osteogenic pathway of the jaw may have better osteogenic ability, and its stem cells have better proliferation and osteogenic differentiation ability. However, the jaw structure is less regular, the osteogenic differentiation ability of its osteoblasts is mineralization slightly weak, and the immune cells of the jaw are more sensitive to cytokines. These may be the reasons why the osseointegration of the jaw implant is different from that of the femur in animal experiments, but its specific mechanism has not been clarified.

Patients seeking implantation often have several systemic diseases, which will introduce complications to treatment. This paper reviews the risk assessments and prevention of systemic diseases in patients with oral implant therapy with the relevant literature. The patients with cardiovascular diseases are prone to stroke and cardiac arrest, and anticoagulants and antihypertensive drugs will complicate cases. The potential risks of endocrine system diseases are infections and crises caused by unstable hormone levels. The risks of respiratory diseases are dyspnea and swallowing devices. The difficulty of treating patients with neuropsychiatric diseases is attributable to poor cooperation and adverse effects of the drugs. Bone and joint system diseases may decrease the success of implantation. Hematological system, digestive system and kidney diseases may lead to hemorrhage. By inquiring about detailed medical and medication history, evaluating vital signs and detecting important objective indicators, performing targeted measures, discussing with specialists, and observing patients closely, clinicians can avoid the abovementioned risks.