OBJECTIVE To investigate the effects of calcitriol on sepsis-induced immunosuppression and its potential mechanism. METHODS A sepsis-induced immunosuppression mice model was established using cecal ligation and puncture （CLP）. The 7-day survival rate， serum levels of tumor necrosis factor- α （TNF- α）， interleukin-6 （IL-6）， and IL-1β were determined in sham operation group， CLP group and calcitriol group （1 μg/kg）； the morphological changes of lung tissue in mice were observed. Lipopolysaccharide （LPS） tolerance macrophage models （representing sepsis-induced immunosuppression） were established using mice macrophage cell line RAW264.7 cells. The levels of TNF-α and IL-6 in cell supernatants as well as mRNA expressions of IL-1β， nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 （NLRP3）， IL-18 and caspase-1 were assessed in culture medium group， LPS group， LPS tolerance group， and calcitriol （5 μmol/L） group. The following parameters were measured： propidium iodide （PI）-positive cell ratio， caspase-1 activity， lactate dehydrogenase （LDH） release， and Ca2+ levels. RESULTS Compared with CLP group， 7-day survival rate and serum levels of TNF-α， IL-6 and IL-1β were increased significantly in calcitriol group （P＜0.05）. Additionally， pulmonary tissue damage was markedly attenuated in calcitriol group. Compared with LPS tolerance group， the levels of TNF-α and IL-6 in cell supernatants， mRNA expressions of IL- 1β， NLRP3， IL-18 and caspase-1， PI-positive cell ratio， caspase-1 activity， LDH release， and Ca2+ levels were all increased significantly in calcitriol group （P＜0.05）. CONCLUSIONS Calcitriol can reverse sepsis-induced immunosuppression， and the mechanism of action may be E-mail：yarfwy@163.com achieved by the binding of calcitriol to vitamin D receptor，which promotes the release of Ca2+ from the endoplasmic reticulum， thereby driving the NLRP3/caspase-1-mediated pyroptosis pathway.

In July 2023， the National Medical Products Administration issued the Measures for the Administration of Standards for Medicinal Products （hereinafter referred to as the Measures）. This article interprets the main content of the Measures， and analyzes its shortcomings as unclear definition of the drug standard code and the goals of drug standard information construction. It is recommended that the national drug regulatory department promptly apply to the standardization authority for the confirmation of the drug standard code “YB” letter， and the drug standard code and numbering rules would be included in the next round of amendments to the Measures. It is necessary to clarify the construction goals of the information system for drug standards at the same time， and build a national drug standard data-sharing platform based on the basic framework of user interface layer， computing processing layer， and data storage layer. Digital drug standards will be free， and access and download services for the public will be provided.

Glucagon-like peptide-1 ( GLP-1 ) is secreted by gut enteroendocrine cells. GLP-1 receptor agonists ( GLP-1 RAs) control glucose-related augmentation of insulin and suppress glu-cagon secretion. GLP-lRAs also inhibit gastric emptying, food intake and limit weight gain. In the past decade, significant progresses have been made in the investigation on the effects of GLP-1 RAs on cardiovascular system. The potential advantages of oral small-molecule GLP-1 RAs could improve the application of this class of drugs. This review highlights the multiple cardiovascular profiles of GLP-1 RAs in the treatment of cardiovascular diseases to provide new insights into cardiovascular benefits of GLP-1 RAs.

Objective To investigate the risk factors of drug resistance in patients with ischemic stroke by clopidogrel therapy and provide references for promoting clinical individualized drug therapy. Methods A total of 202 inpatients diagnosed with ischemic stroke were admitted and given dual anti-treatment (aspirin+clopidogrel). CYP2C19 genotype was detected by microarray hybridization during hospitalization, and CYP2C19 gene polymorphisms were classified into fast metabolism group, medium metabolism group and slow metabolism group according to the type of drug metabolism. Patients were tested for platelet inhibition induced by adenosine diphosphate (ADP) according to thromboelastographic (TEG) on 7~14 d of drug administration. ADP <30% was classified as clopidogrel drug resistance group and ADP ≥30% as non-resistance group. Logistic regression analysis was used to study the risk factors for the development of clopidogrel resistance. Results Among 202 patients with ischemic stroke, 87 were in the resistant group and 115 in the non-resistant group. The proportion of patients with clopidogrel resistance combined with diabetes and the level of white blood cell count were higher than that in the non-resistant group, and the differences were statistically significant (P<0.05).The proportion of patients with clopidogrel resistance in the CYP2C19 intermediate metabolism group was significantly higher than that in the fast metabolism group, and the rate of platelet inhibition was also significantly lower than that in the fast metabolism group, all with statistically significant differences (P<0.05). Conclusion Combined diabetes mellitus, high white blood cell count levels and CYP2C19 mid-metabolic phenotype are independent risk factors for the development of clopidogrel resistance in patients with ischemic stroke.

There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor 4 (M₄) in schizophrenia and dementia with Lewy bodies, however, a clinically validated M₄ positron emission tomography (PET) radioligand is currently lacking. As such, the aim of this study was to develop a suitable M₄ PET ligand that allows the non-invasive visualization of M₄ in the brain. Structure-activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound 12 - a subtype-selective positive allosteric modulator (PAM). The radiofluorinated analogue, [¹⁸F] 12, was synthesized in 28 ± 10% radiochemical yield, >37 GBq/μmol and an excellent radiochemical purity >99%. Initial in vitro autoradiograms on rodent brain sections were performed in the absence of carbachol and showed moderate specificity as well as a low selectivity of [¹⁸F] 12 for the M₄-rich striatum. However, in the presence of carbachol, a significant increase in tracer binding was observed in the rat striatum, which was reduced by >60% under blocking conditions, thus indicating that orthosteric ligand interaction is required for efficient binding of [¹⁸F] 12 to the allosteric site. Remarkably, however, the presence of carbachol was not required for high specific binding in the non-human primate (NHP) and human striatum, and did not further improve the specificity and selectivity of [¹⁸F] 12 in higher species. These results pointed towards significant species-differences and paved the way for a preliminary PET study in NHP, where peak brain uptake of [¹⁸F] 12 was found in the putamen and temporal cortex. In conclusion, we report on the identification and preclinical development of the first radiofluorinated M₄ PET radioligand with promising attributes. The availability of a clinically validated M₄ PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging.

OBJECTIVE: To investigate the inhibitory effect of ANA-12 that blocks brain-derived neurotrophic factor (BDNF)/ tropomyosin receptor kinase B (TrkB) signaling on inflammatory pain in rats and explore the underlying mechanism. METHODS: Forty-two adult SD rats were randomized into BDNF-induced acute pain group (n=24) and CFA-induced chronic pain group. The former group were randomly divided into 4 subgroups, including a control group, ANA-12 treatment group, BDNF treatment group, and BDNF+ANA-12 treatment group; the latter group were subgrouped into control group, CFA treatment group (CFA) and CFA + ANA-12 treatment group. The effects of ANA-12 treatment on pain behaviors of the rats with BDNF-induced acute pain and CFA-induced chronic inflammatory pain were observed. Western blotting was used to examine TrkB signaling and expressions of microglia marker protein Iba1 and TNF-α in the spinal cord of the rats. RESULTS: BDNF injection into the subarachnoid space significantly increased the number of spontaneous paw withdrawal of the rats (P < 0.05), which was obviously reduced by ANA-12 treatment (P < 0.05). The rats with intraplantar injection of CFA, showed significantly increased ipsilateral mechanical stimulation sensitivity (P < 0.05), and ANA-12 treatment obviously increased the ipsilateral foot withdrawal threshold (P < 0.05). Treatment with either BDNF or CFA significantly increased the phosphorylation level of TrkB (Y705) in the spinal cord of the rats (P < 0.05), which was significantly lowered by ANA-12 treatment (P < 0.05). Treatment with BDNF and CFA both significantly up-regulated the expressions of Iba1 and TNF-α in the spinal cord (P < 0.05), but ANA-12 significantly reduced their expression levels (P < 0.05). CONCLUSION ANA-12 can reduce spinal cord inflammation and relieve acute and chronic pain in rats by targeted blocking of BDNF/TrkB signaling.
Animals ; Brain-Derived Neurotrophic Factor/metabolism* ; Chronic Pain/drug therapy* ; Inflammation ; Rats ; Rats, Sprague-Dawley ; Receptor, trkB/metabolism*

OBJECTIVE：To unscramble the Notice on Standardizing the Allocation and Use of Licensed Pharmacists in Drug Retail Enterprises （called Notice for short ）and related document ，and to give some suggestions to provide reference for the industry and policy decision departments. METHODS ：The background and content of Notice were described briefly ；the problemsexisting in the corresponding provincial differentiated allocation policy and the difficulties existing in the implementation were analyzed to give some relevant suggestions. RESULTS & CONCLUSIONS ：The main contents of Notice contained adhering to the policy of licensed pharmacists ，steadily improving the allocation level of licensed pharmacists ，refining and implementing the allocation requirements ，and strengthening the implementation of supervision and inspection responsibilities ；giving full play to the role of licensed pharmacists and continuously strengthening the team building. At present ，drug administrations of many provinces in China have issued specific policies on the differentiated allocation of licensed pharmacists and pharmaceutical technicians ，which are mainly divided into four schemes. The author believes that the classification method of drug retail enterprises implemented in Shandong and Guangdong provinces are the most scientific. The implementation of differentiated allocation of pharmacists with health（pharmacy）professional title in drug retail enterprises can alleviate the problem of insufficient licensed pharmacists to a certain extent ，but the disadvantage is that it can not achieve accurate registration and control as well as the management of licensed pharmacists ，which is easy to produce policy gaps ；after the “affiliation licensed pharmacist ’s certificate ”phenomenon， the“certificate affiliation of pharmacist with health （pharmacy）professional title ”phenomenon appeared. It is suggested that the provincial drug supervision and administration departments should try the differentiated allocation scheme of hierarchical management；learn from the management experience of licensed pharmacists and pharmaceutical technicians in Guangdong province， develop relevant platforms to manage the information of pharmaceutical technicians uniformly ； strengthen the communication and interaction with the health and human resource security department as well as the mutual promotion mechanism of personnel information screening ，so as to solve the core bottleneck of licensed pharmacists ’quality.

OBJECTIVE: To analyze the clinical and genetic features of three patient diagnosed with Kleefstra syndrome. METHODS: Whole exome sequencing (WES) was carried out for the probands and their parents. Suspected variants were validated by Sanger sequencing. Copy number variations (CNV) were detected by CNV-seq and validated by real-time PCR. RESULTS: Proband 1 was found to carry a de novo heterogeneous variant (c.823+1G>T) of the EHMT1 gene, which may affect its expression. Based on the guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be pathogenic (PVS1+PS2+PM2). Proband 2 was found to carry a de novo missense variant c.439C>G (p.L147V) of the EHMT1 gene, which was predicted to be likely pathogenic (PS2+PM1+PM2+PP3). Proband 3 was found to carry a heterozygous 520 kb deletion at 9q34.3 by CNV-seq. The deletion has encompassed the whole of the EHMT1 gene. Real-time PCR has detected no CNV of this region in her parents. CONCLUSION Variants of the EHMT1 gene probably underlay the disease in these patients. Genetic testing has provided a basis for their clinical diagnosis.
Chromosome Deletion ; Chromosomes, Human, Pair 9 ; Craniofacial Abnormalities ; DNA Copy Number Variations ; Female ; Genetic Testing ; Heart Defects, Congenital ; Humans ; Intellectual Disability/genetics* ; Mutation

Objective To investigate the residential radon concentration in typical areas of Hubei Province and assess the dose hazards of radon to human body. Methods According to geographical location, five cities including Wuhan, Enshi, Shiyan, Xianning and Daye were selected, and the stratified cluster sampling and monitoring were conducted in accordance with the residential building structure. From April to July, 2019, RSKS standard detectors were placed in the bedroom or living room of the tested families. After continuously sampling for three months, those detectors were returned back to the laboratory for test readings using Radosys system. Results A total of 651 detectors were deployed in 577 households of 70 communities, and 634 detectors were recovered. The recovery rate of detectors was 97.4%. The indoor residential radon concentration in Hubei Province showed a logarithmic normal distribution, with a median (25% quantile and 75% quantile) of 40.52 (29.13,64.74) Bq/m3 and an annual effective dose of 2.02 mSv. The indoor radon concentrations in Wuhan and Enshi were significantly higher than those in Shiyan, Xianning and Daye (P<0.05). The indoor radon concentrations in brick wood or civil structures were significantly higher than those in reinforced concrete structures (P<0.05), and indoor radon concentration in the first floor was significantly higher than those in other floors (P<0.05). The indoor radon concentrations after 2010 were significantly lower than those between 2001 and 2010 (P<0.05). Conclusion The number of households with indoor radon concentrations exceeding the national limit in newly-built buildings accounted for 10.1%; The indoor residential radon concentration levels of in Hubei Province were influenced by building structure, age and floor.

OBJECTIVE: To delineate the clinical feature and genetic basis of four patients with congenital neutropenia. METHODS: All patients were subjected to whole exome sequencing (WES). Suspected variants were verified by Sanger sequencing. RESULTS: The patients (two boys and two girls), aged 7 to 15 months, suffered from neutropenia and recurrent infections. Bone marrow smears showed a significant decrease in the proportion of rod-shaped and lobulated granulocytes, which suggested impaired development and maturation of bone marrow neutrophils. WES has discovered heterozygous variants (c.496G>A, c.58C>G, c.391G>A and IVS1+5T>A) of the ELANE gene in the patients. Among these, c.58C>G and IVS1+5T>A were unreported previously. Follow up revealed patients 1 and 3 had periodic neutropenia, while patients 2 and 4 had severe congenital neutropenia. After attaining the definite diagnosis, the patients were treated symptomatically. CONCLUSION The main clinical feature of congenital neutropenia is refractory recurrent bacterial infections, for which mutations of the ELANE gene are a common cause. Two novel pathogenic ELANE variants have been discovered in this study.
Congenital Bone Marrow Failure Syndromes/genetics* ; Female ; Genetic Testing ; Humans ; Infant ; Leukocyte Elastase/genetics* ; Male ; Mutation ; Neutropenia/genetics*