Stimulation of mouse hematopoietic stem cells by angiogenin and DNA preparations

Immature hematopoietic progenitors are a constant source for renewal of hemocyte populations and the basic component of the tissue and cell repair apparatus. A unique property of these cells of internalizing extracellular double-stranded DNA has been previously shown. The leukostimulatory effect demonstrated in our pioneering studies was considered to be due to the feature of this cell. In the present research, we have analyzed the effects of DNA genome reconstructor preparation (DNAgr), DNAmix, and human recombinant angiogenin on both hematopoietic stem cells and multipotent progenitors. Treatment with bone marrow cells of experimental mice with these preparations stimulates colony formation by hematopoietic stem cells and proliferation of multipotent descendants. The main lineage responsible for this is the granulocyte-macrophage hematopoietic lineage. Using fluorescent microscopy as well as FACS assay, co-localization of primitive c-Kit- and Sca-1-positive progenitors and the TAMRA-labeled double-stranded DNA has been shown. Human recombinant angiogenin was used as a reference agent. Cells with specific markers were quantified in intact bone marrow and colonies grown in the presence of inducers. Quantitative analysis revealed that a total of 14,000 fragment copies of 500 bp, which is 0.2% of the haploid genome, can be delivered into early progenitors. Extracellular double-stranded DNA fragments stimulated the colony formation in early hematopoietic progenitors from the bone marrow, which assumed their effect on cells in G0. The observed number of Sca1+/c-Kit+ cells in colonies testifies to the possibility of both symmetrical and asymmetrical division of the initial hematopoietic stem cell and its progeny.

Investigation of the molecular genetic causes of non-syndromic primary ovarian ınsufficiency by next generation sequencing analysis

ABSTRACT Objective: The aim of this study is to investigate the molecular genetic causes of non-syndromic primary ovarian insufficiency (POI) cases with the gene panel based on next generation sequencing analysis and to establish the relationship between genotype and phenotype. Subjects and methods: Twenty three cases aged 14-40 years followed up with POI were included. Patients with a karyotype of 46, XX, primary or secondary amenorrhea before the age of 40, with elevated FSH (>40 IU/mL) and low AMH levels (<0.03 ng/mL) were included in the study. Molecular genetic analyzes were performed by the next generation sequencing analysis method targeted with the TruSightTM Exome panel. Results: Median age of the cases was 17.8 (14.0-24.3) years, and 12 (52%) cases admitted before the age of 18. Fifteen (65%) patients had consanguineous parents. In 2 (8.6%) cases, variants detected were in genes that have been previously proven to cause POI. One was homozygous variant in FIGLA gene and the other was homozygous variant in PSMC3IP gene. Heterozygous variants were detected in PROK2, WDR11 and CHD7 associated with hypogonadotropic hypogonadism, but these variants are insufficient to contribute to the POI phenotype. Conclusion: Genetic panels based on next generation sequencing analysis technologies can be used to determine the molecular genetic diagnosis of POI, which has a highly heterogeneous genetic basis.

Morphometry of the Middle Cerebral Arteries: A Radio-Anatomical Study Based on Computed Tomography Angiography Findings / Morfometría de las Arterias Cerebrales Medias: Un Estudio Anátomo-Radiológico Basado en los Hallazgos de la Angiografía por Tomografía Computada

SUMMARY: Middle cerebral artery (MCA), which has the largest irrigation area of the arteries that feed the brain, is an important artery whose microanatomy should be well known because of its vascular variation. In pathologies which are known to affect the cerebrovascular system such as type 2 diabetes mellitus (T2DM) and hypertension, morphometric characteristics of MCA gain importance. The aim of this study is to compare the morphometric characteristics of M1 segment of MCA in T2DM and hypertensive patients with those of healthy control group by using computed tomographic angiography (CTA). The study was carried out with retrospective morphometric analysis of CTA images of 200 individuals between 40 and 65 years of age. The individuals were grouped in four as hypertensive patients (group 1), patients with T2DM (group 2), patients with hypertension and T2DM (group 3) and healthy control group (group 4). Length and diameter measurements of M1 segment were performed and recorded by using 3D CTA images. While statistically significant difference was found between bilateral M1 segment diameters of both women and men (p0.05). As a result of the post hoc analysis performed, it was concluded that right and left M1 segment diameter of group 1, group 2 and group 3 was found to be different from group 4 in both sexes (p<0.05). We believe that this study will both be a guide in radio-anatomic assessments to be performed and also increase microanatomic level of information in the surgical treatment of the artery by showing the morphometric changes that occur in M1 segment of MCA in T2DM diseases.

La arteria cerebral media (ACM), que otorga la mayor área de irrigación de las arterias que alimentan el cerebro, es un vaso importante cuya microanatomía debe ser bien conocida por su variación vascular. En patologías que afectan al sistema cerebrovascular, como la diabetes mellitus tipo 2 (DM2) y la hipertensión, las características morfométricas de la ACM cobran importancia. El objetivo de este estudio fue comparar las características morfométricas del segmento M1 de la ACM en pacientes con DM2 e hipertensos con las del grupo control sano mediante el uso de angiografía por tomografía computada (TC). El estudio fue realizado através de análisis morfométrico retrospectivo de imágenes de TC de 200 individuos entre 40 y 65 años de edad. Los individuos fueron divididos en cuatro grupos, como pacientes hipertensos (grupo 1), pacientes con DM2 (grupo 2), pacientes con hipertensión y DM2 (grupo 3) y grupo control sano (grupo 4). Las mediciones de longitud y diámetro del segmento M1 se realizaron y registraron utilizando imágenes 3D TC. Si bien se encontraron diferencias estadísticamente significativas entre los diámetros bilaterales de los segmentos M1 de mujeres y hombres (p0,05). Como resultado del análisis post hoc realizado, se concluyó que el diámetro de los segmentos M1 derecho e izquierdo del grupo 1, grupo 2 y grupo 3 fue diferente del grupo 4 en ambos sexos (p<0.05). Creemos que este estudio será una guía en las evaluaciones anátomo-radiológicas y también mejorará el nivel de información microanatómica en el tratamiento quirúrgico al mostrar los cambios morfométricos que ocurren en el segmento M1 de la ACM en las enfermedades con DM2.

Principles and Practices of Effective Food Safety Risk Communication – Introducing the Asia-Pacific Economic Cooperation Food Safety Risk Communication Framework

This paper describes the principles and practices of effective food safety risk communication developed under the “Asia-Pacific Economic Cooperation Food Safety Risk Communication Framework and Associated Guidelines”. The framework recommends that effective food safety risk communication needs to be centered on the clear goal of protecting consumer health by ensuring transparency and timeliness, and communication on food safety matters should be conducted in a two-way process. It emphasizes the need to provide the public with credible information based on science and evidence and highlights that food safety is a shared responsibility among all stakeholders, including industry, government agencies, media organizations and consumers. It further highlights that food safety risk communication needs to be conducted in a consistent, systematic, inclusive, consultative, and preventative manner. The framework also indicates that effective food safety risk communication needs to pay attention to the backgrounds, experiences, and needs of concerned audiences. It stresses the importance of continuous improvement of the communication system to ensure food safety risk communication to be effective. Focusing on effective communications in response to food safety incidents, emergency or crisis situations, as well as everyday food safety communications, these principles and practical guidelines will help food safety regulators, food industry, food safety educators and other stakeholders improve their communications with target audiences.

Therapeutic Window of Intravenous Immunoglobulin (IVIG) and its correlation with IVIG-resistant in Kawasaki Disease: a retrospective study

Abstract Objective: To investigate the optimal timing of initial intravenous immunoglobulin (IVIG) treatment in Kawasaki disease (KD) patients. Methods: KD patients were classified as the early group (day 1-4), conventional group (day 5-7), conventional group (day 8-10), and late group (after day 10). Differences among the groups were analyzed by ANOVA and Chi-square analysis. Predictors of IVIG resistance and the optimal cut-off value were determined by multiple logistic regression analyses and receiver operating characteristic (ROC) curve analysis. Results: There were no significant differences in IVIG resistance among the 4 groups (p = 0.335). The sensitivity analysis also confirmed no difference in the IVIG resistance between those who started the initial IVIG ≤ day 7 of illness and those who received IVIG >day 7 of illness (p = 0.761). In addition, patients who received IVIG administration more than 7 days from the onset had a higher proportion of coronary artery abnormalities (p = 0.034) and longer length of hospitalization (p = 0.033) than those who started IVIG administration less than 7 days. The optimal cut-off value of initial IVIG administration time for predicting IVIG resistance was >7 days, with a sensitivity of 75.25% and specificity of 82.41%. Conclusions: IVIG therapy within 7 days of illness is found to be more effective for reducing the risk of coronary artery abnormalities than those who received IVIG >day 7 of illness. IVIG treatment within the 7 days of illness seems to be the optimal therapeutic window of IVIG. However, further prospective studies with long-term follow-up are required.

Assessment of Left Ventricular Diastolic Dysfunction in Cases with Liver Cirrhosis

Background: Cirrhosis is a long-term inflammatory process of hepatic tissue condition that mainly affects people aged 50 to 60. This study aims to assess Left ventricular diastolic dysfunction (LVDD) in cases with cirrhotic liver by conventional, tissue Doppler and two-dimensional speckle tracking echocardiography to clarify the correlation between the severity of cirrhotic liver and LVDD. Methods: A prospective case-control research involved 100 adult cases with confirmed HCV and HBV. Cases were divided into 4 equal group: Group A: Child A cases, group B: Child B cases, group C: Child C cases and group D (Controls): healthy non-hepatic subjects of the same age and sex who have normal blood pressure, nonsmoking participants with no further concomitant problems. Results: Number of cases with LVDD had a statistical noticeable increase in Child A, B, and C (p =0.004, <0.001, and <0.001 respectively. LAVi had a statistical noticeable increase in Child C / B (p =0.013 and p =0.014). Conclusion: Left atrial volume index (LAVi) had a statistical noticeable increase in Child C / B in comparison to the controls but E m, E l were statistical noticeable lower in Child C / B. /E had a statistical noticeable increase in Child C group, LVSRe had a statistical noticeable decrease in Child C group but it was insignificantly different across Child A / B/ C and controls and across Child B / C and controls.

Existence of advanced glycation / lipoxidation end-products in parenteral nutrition solutions and effects of infusion conditions on their levels

Abstract Infusion solutions must be stable from the production stage until the infusion stage. Some infusion fluids contain degradation products, known as advanced glycation end products (AGEs); however, it is unknown whether AGEs exist in parenteral nutrition solutions. We aimed to investigate this question and test the effect of infusion conditions on AGE formation in parenteral nutrition solution. Nine parenteral nutrition solutions were supplied by the pharmacy with which we collaborated. To simulate the infusion conditions, the solutions were held in a patient room with standard lighting and temperature for 24 hours. Samples were taken at the beginning (group A) and the end (24th hour, group B) of the infusion period. The degradation products were 3-deoxyglucosone, pentosidine, N-carboxymethyl lysine, and 4-hydroxynonenal, which we investigated by high-performance liquid chromatography-mass spectrometry (LC-MS) and Q-TOF LC/MS methods. Two of four degradation products, 4-hydroxynonenal and N-carboxymethyl lysine, were detected in all samples, and Group B had higher levels of both compounds compared to Group A, who showed that the quantities of these compounds increased in room conditions over time. The increase was significant for 4-hydroxynonenal (p=0.03), but not for N-carboxymethyl lysine (p=0.23). Moreover, we detected in the parenteral nutrition solutions a compound that could have been 4-hydroxy-2-butynal or furanone

Fixation methods in latarjet: biomechanical comparison of screw types and plate fixation / Métodos de fixação em latarjet: comparação de tipos de parafusos e fixação de placas

ABSTRACT Objective Latarjet procedure is often preferred in recurrent shoulder dislocations accompanied by glenoid bone loss. It is observed that the superiority of bone graft fixation methods is still controversial. The aim of this study is to biomechanically compare the bone graft fixation methods in the Latarjet procedure. Methods 15 third-generation scapula bone models were divided into 3 groups. Graft was fixated in the first group with fully-threaded cortical screws of 3.5mm diameter, in the second group two 16 mm partially-threaded cannulated screws of 4.5mm diameter, and in the third group via a mini plate and screw. The hemispherical humeral head was placed on the tip of the cyclic charge device, and thus, the charge applied to the coracoid graft was homogeneous. Results No statistically significant difference was found between paired comparisons (p>0.05). The forces in 5 mm displacement in total vary between 502-857N. Total stiffness measurements ranged between 105 and 625; the mean value was 258.13±53.54 with no statistically significant difference by groups (p = 0.958). Conclusion This biomechanical study showed that there is no difference between three coracoid fixation options in terms of fixation strength. Unlike previous assumptions, plate fixation is not biomechanically superior to screw fixation. Surgeons should consider their personal preferences and experience in choosing fixation methods.

RESUMO Objetivo O procedimento Latarjet é normalmente preferencial em deslocamentos recorrentes do ombro acompanhados por perda óssea da glenóide. Observa-se que a superioridade dos métodos de fixação dos enxertos ósseos ainda é controversa. O objetivo deste estudo é comparar biomecanicamente os métodos de fixação de enxerto ósseo no procedimento Latarjet. Métodos 15 modelos de escápulas de terceira geração foram divididos em 3 grupos. O enxerto foi fixado no primeiro grupo com parafusos corticais totalmente rosqueados com 3,5 mm de diâmetro, no segundo grupo com dois parafusos canulados parcialmente rosqueados de 16 mm de diâmetro de 4,5 mm e no terceiro grupo através de miniplaca e parafuso. A cabeça hemisférica umeral foi colocada na ponta do dispositivo de carga cíclica e, desta forma, a carga aplicada ao enxerto coracoide foi homogênea. Resultados Nenhuma diferença estatisticamente significativa foi encontrada entre as comparações pareadas (p>0,05). As forças em 5 mm de deslocamento no total variam entre 502-857N. As medidas de rigidez total variaram entre 105 e 625 e o valor médio foi 258,13±53,54, sem diferença estatisticamente significativa por grupos (p = 0,958). Conclusão Este estudo biomecânico mostrou que não há diferença entre três opções de fixação de coracoides em termos de resistência à fixação. Ao contrário de suposições anteriores, a fixação de placas não é biomecanicamente superior à fixação de parafusos. Os cirurgiões devem considerar suas preferências pessoais e sua experiência na escolha de métodos de fixação.

Metastatic diffuse follicular variant papillary thyroid cancer without cervical lymph node metastasis presenting with symptoms related to hypopituitarism

ABSTRACT In this article, we present a case of diffuse follicular variant papillary thyroid carcinoma with pituitary metastasis, which is a rare cause of pituitary metastasis. The follicular variant of papillary thyroid carcinoma is an uncommon variant of papillary carcinoma. A 74-year-old male was presented with weakness, fatigue, and a decreased appetite. The patient was diagnosed with secondary adrenal and thyroid insufficiencies. Imaging revealed a pituitary mass with suprasellar extension, right cavernous sinus invasion, and optic chiasm compression. Thyroid ultrasonography revealed a nodule with a maximum size of 7.2cm in the right lobe. Cytological examination via fine-needle aspiration suggested papillary thyroid cancer. Total thyroidectomy with central and right lateral neck dissection confirmed the diagnosis of diffuse follicular variant of papillary thyroid carcinoma. Owing to visual field defects, the patient underwent transsphenoidal surgery. Histological and immunohistochemical evaluations confirmed pituitary metastasis from the papillary thyroid cancer. Radioactive iodine treatment and gamma knife radiotherapy of the pituitary gland were performed. The initiation of sorafenib treatment was deemed appropriate during the follow-up. A significant decrease in the thyroglobulin levels was observed after sorafenib treatment. Pituitary metastasis should be considered in patients diagnosed with hypopituitarism and pituitary lesions at initial evaluation. The presence of visual field defects may be an indication for neurosurgical intervention and guide both diagnosis and treatment. The management of papillary thyroid cancer and the role of treatment modalities in prognosis depend on the biological behavior of the tumor. Early diagnosis and multidisciplinary management are crucial for the treatment of these patients.

Perillyl alcohol modulates activation, permeability and integrity of human brain endothelial cells induced by Plasmodium falciparum

BACKGROUND Cerebral malaria (CM) is a severe immunovasculopathy caused for Plasmodium falciparum infection, which is characterised by the sequestration of parasitised red blood cells (pRBCs) in brain microvessels. Previous studies have shown that some terpenes, such as perillyl alcohol (POH), exhibit a marked efficacy in preventing cerebrovascular inflammation, breakdown of the brain-blood barrier (BBB) and brain leucocyte accumulation in experimental CM models. OBJECTIVE To analyse the effects of POH on the endothelium using human brain endothelial cell (HBEC) monolayers co-cultured with pRBCs. METHODOLOGY The loss of tight junction proteins (TJPs) and features of endothelial activation, such as ICAM-1 and VCAM-1 expression were evaluated by quantitative immunofluorescence. Microvesicle (MV) release by HBEC upon stimulation by P. falciparum was evaluated by flow cytometry. Finally, the capacity of POH to revert P. falciparum-induced HBEC monolayer permeability was examined by monitoring trans-endothelial electrical resistance (TEER). FINDINGS POH significantly prevented pRBCs-induced endothelial adhesion molecule (ICAM-1, VCAM-1) upregulation and MV release by HBEC, improved their trans-endothelial resistance, and restored their distribution of TJPs such as VE-cadherin, Occludin, and JAM-A. CONCLUSIONS POH is a potent monoterpene that is efficient in preventing P. falciparum-pRBCs-induced changes in HBEC, namely their activation, increased permeability and alterations of integrity, all parameters of relevance to CM pathogenesis.

Preparation of Huoluo Xiaoling gel plaster and its transdermal penetration in vitro / 中国中药杂志

Huoluo Xiaoling Dan is a classical prescription commonly used for blood circulation and pain relief in clinic with obvious effects. To make it directly treat lesion and improve the effect, this research optimized the preparation process of Huoluo Xiaoling gel paste and further evaluated its in vitro transdermal absorption performance, so as to provide a scientific basis for its development and utilization. Using primary viscosity, holding viscosity, and sensory score as evaluation indexes, the matrix amount of gel paste was determined by the single factor test and Box-Behnken response surface method. The ultra-performance liquid chromatography(UPLC) method was established to determine the content of eight active ingredients, including Danshensu, ferulic acid, salvianolic acid B, salvianolic acid A, ligustilide, tanshinone Ⅱ_A, 11-keto-β-boswellic(KBA), and 3-acetyl-11-keto-β-boswellic acid(AKBA). A mo-dified Franz diffusion cell method was used to evaluate and compare the absorption properties of the gel paste without volatile oil and with volatile oil microemulsion. The results showed that the optimal prescription for Huoluo Xiaoling gel paste matrix was NP700(1.35 g), glycerol(7.00 g), micropowder silica gel(1.25 g), sodium carboxymethyl cellulose(0.20 g), tartaric acid(0.06 g), and glyceryl aluminum(0.04 g). The mass fractions of eight active ingredients in the paste were successively 0.48, 0.014, 0.95, 0.39, 0.57, 0.055, 0.35, and 0.97 mg·g~(-1). The results of the in vitro transdermal absorption test showed that the addition of the volatile oil or the volatile oil microemulsion promoted the transdermal absorption of the active ingredients, and the law of drug penetration conformed to the zero equation or the Higuchi equation. The gel paste prepared by the optimal prescription has good appearance and adhesion, with no residue, and has the characteristics of skeletal slow-release preparation, which is easy to reduce the number of administration, la-ying a foundation for the development of new external dosage forms of Huoluo Xiaoling Dan.

Effect of Morus alba extract sanggenon C on growth and proliferation of glioblastoma cells / 中国中药杂志

Glioblastoma is the most common primary cranial malignancy, and chemotherapy remains an important tool for its treatment. Sanggenon C(San C), a class of natural flavonoids extracted from Morus plants, is a potential antitumor herbal monomer. In this study, the effect of San C on the growth and proliferation of glioblastoma cells was examined by methyl thiazolyl tetrazolium(MTT) assay and 5-bromodeoxyuridinc(BrdU) labeling assay. The effect of San C on the tumor cell cycle was examined by flow cytometry, and the effect of San C on clone formation and self-renewal ability of tumor cells was examined by soft agar assay. Western blot and bioinformatics analysis were used to investigate the mechanism of the antitumor activity of San C. In the presence of San C, the MTT assay showed that San C significantly inhibited the growth and proliferation of tumor cells in a dose and time-dependent manner. BrdU labeling assay showed that San C significantly attenuated the DNA replication activity in the nucleus of tumor cells. Flow cytometry confirmed that San C blocked the cell cycle of tumor cells in G_0/G_1 phase. The soft agar clone formation assay revealed that San C significantly attenuated the clone formation and self-renewal ability of tumor cells. The gene set enrichment analysis(GSEA) implied that San C inhibited the tumor cell division cycle by affecting the myelocytomatosis viral oncogene(MYC) signaling pathway. Western blot assay revealed that San C inhibited the expression of cyclin through the regulation of the MYC signaling pathway by lysine demethylase 4B(KDM4B), which ultimately inhibited the growth and proliferation of glioblastoma cells and self-renewal. In conclusion, San C exhibits the potential antitumor activity by targeting the KDM4B-MYC axis to inhibit glioblastoma cell growth, proliferation, and self-renewal.

Faculty perceptions regarding an individually tailored, flexible length, outcomes-based curriculum for undergraduate medical students / 한국의학교육

Purpose@#The perception of faculty members about an individually tailored, flexible-length, outcomes-based curriculum for undergraduate medical students was studied. Their opinion about the advantages, disadvantages, and challenges was also noted. This study was done to help educational institutions identify academic and social support and resources required to ensure that graduate competencies are not compromised by a flexible education pathway. @*Methods@#The study was done at the International Medical University, Malaysia, and the University of Lahore, Pakistan. Semi-structured interviews were conducted from 1st August 2021 to 17th March 2022. Demographic information was noted. Themes were identified, and a summary of the information under each theme was created. @*Results@#A total of 24 (14 from Malaysia and 10 from Pakistan) faculty participated. Most agreed that undergraduate medical students can progress (at a differential rate) if they attain the required competencies. Among the major advantages mentioned were that students may graduate faster, learn at a pace comfortable to them, and develop an individualized learning pathway. Several logistical challenges must be overcome. Providing assessments on demand will be difficult. Significant regulatory hurdles were anticipated. Artificial intelligence (AI) can play an important role in creating an individualized learning pathway and supporting time-independent progression. The course may be (slightly) cheaper than a traditional one. @*Conclusion@#This study provides a foundation to further develop and strengthen flexible-length competency-based medical education modules. Further studies are required among educators at other medical schools and in other countries. Online learning and AI will play an important role.

Artificial Intelligence in the Prediction of Gastrointestinal Stromal Tumors on Endoscopic Ultrasonography Images: Development, Validation and Comparison with Endosonographers

Background/Aims@#The accuracy of endosonographers in diagnosing gastric subepithelial lesions (SELs) using endoscopic ultrasonography (EUS) is influenced by experience and subjectivity. Artificial intelligence (AI) has achieved remarkable development in this field. This study aimed to develop an AI-based EUS diagnostic model for the diagnosis of SELs, and evaluated its efficacy with external validation. @*Methods@#We developed the EUS-AI model with ResNeSt50 using EUS images from two hospitals to predict the histopathology of the gastric SELs originating from muscularis propria. The diagnostic performance of the model was also validated using EUS images obtained from four other hospitals. @*Results@#A total of 2,057 images from 367 patients (375 SELs) were chosen to build the models, and 914 images from 106 patients (108 SELs) were chosen for external validation. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the model for differentiating gastrointestinal stromal tumors (GISTs) and non-GISTs in the external validation sets by images were 82.01%, 68.22%, 86.77%, 59.86%, and 78.12%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in the external validation set by tumors were 83.75%, 71.43%, 89.33%, 60.61%, and 80.56%, respectively. The EUS-AI model showed better performance (especially specificity) than some endosonographers.The model helped improve the sensitivity, specificity, and accuracy of certain endosonographers. @*Conclusions@#We developed an EUS-AI model to classify gastric SELs originating from muscularis propria into GISTs and non-GISTs with good accuracy. The model may help improve the diagnostic performance of endosonographers. Further work is required to develop a multi-modal EUS-AI system.

In vivo delivery process and regulating mechanisms of lipid-based nanomedicines / 药学学报

Lipid-based nanocarrier is a classic drug delivery system with great biocompatibility and biodegradability. It can effectively reduce the toxicity of anti-tumor and anti-infective drugs in clinical practice. However, it has not yet met the clinical demand for enhanced therapeutic efficacy, and the clinical application is still very limited. The complex in vivo delivery process of lipid-based nanomedicine and the reciprocal interactions with body lead to unexpected changes in in vivo performance of nanomedicine and seriously hinder clinical translation. Therefore, the in-depth study of the relationships among intrinsic properties of lipid-based nanomedicine, the in vivo delivery process, and the regulatory mechanisms will not only provide guidance for the rational design of nanocarriers, but also promote the clinical translation and precision medicine of new lipid-based nanomedicine. In this review, we summarize the in vivo delivery process, regulating factors and intervention strategies for the in vivo delivery of lipid-based nanomedicine.

Preparation, crystal structure and thermostability of nirmatrelvir polymorphs / 药学学报

The polymorphism and thermostability of nirmatrelvir, the main antiviral component of the oral COVID-19 treatment drug, were studied. Four polymorphs of nirmatrelvir were prepared by recrystallization methods. Among them, Form 1 and nirmatrelvir methyl tert-butyl ether solvate (Form 2) had been reported in the literature, while nirmatrelvir isobutyl acetate solvate (NMTW-IBAC) and nirmatrelvir ethyl acetate solvate (NMTW-EA) are two new solvates. The crystal structures were characterized by single-crystal X-ray diffraction, powder X-ray diffraction, thermogravimetric analysis and differential scanning calorimetry. The thermostability of polymorphism and crystalline transformation were also investigated by combining Hirshfeld surface analysis and interaction energy analysis. The results showed that nirmatrelvir Form 1 belongs orthorhombic crystal system with the space group P212121 and one nirmatrelvir molecule included in the asymmetric unit, which has the same crystal structure as nirmatrelvir Form 4 reported in the literature. Owing to its larger thermal expansion, the differences in crystallographic parameters obtained at different temperatures were found between Form 1 and Form 4. Three solvates of nirmatrelvir belonged to the iso-structural with monoclinic crystal system and the space group P21, in which the asymmetric unit contains one nirmatrelvir molecule and one solvent molecule. The thermal analysis results showed that nirmatrelvir Form 1 was a solvent-free crystal form with the best thermal stability and the strongest intermolecular hydrogen bonding. Among the three solvates, NMTW-EA has the worst thermal stability and the weakest hydrogen bonding interaction between the nirmatrelvir molecule and the solvent molecule. The energy framework of nirmatrelvir solvates showed that the closer the arrangement between solvent and nirmatrelvir molecules, the greater the total interaction energy between solvent and nirmatrelvir molecules. The phase transition studies of the three solvates showed that NMTW-IBAC and NMTW-EA were transformed into amorphous after desolvation, respectively, while Form 2 undergoes oiling during desolvation. The research provides theoretical guidance for the analysis, identification and quality control of nirmatrelvir polymorphs.

Mining Novel Anti-Nocardia Drug Targets Based on Pan-genomics and Subtractive Proteomics / 中山大学学报(医学科学版)

ObjectiveNocardia is an apathogen that causes opportunistic infections in humans and has a global distribution. In recent years， resistance of Nocardia to commonly used drugs have been observed， highlighting the urgent need for the identification of new drug targets and the development of novel antimicrobial agents against Nocardia. MethodsThirty-one complete genome sequences of Nocardia strains were retrieved from the GenBank database. Pan-genomic analysis was performed using BPGA， and drug target candidates were screened using subtractive proteomics. Homology modeling was employed to predict the 3D structures of target proteins， and potential drugs targeting these proteins were predicted using DrugBank. Molecular docking techniques were utilized to validate the binding activity between the drugs and target proteins. ResultsThe pan-genomic analysis of the 31 Nocardia strains revealed 1 421 core proteins. Fifteen candidate drug target proteins were identified through subtractive proteomics analysis. Among them， the physicochemical properties of the OG1493 protein （such as amino acid count， molecular weight， isoelectric point， grand average of hydropathicity， fat index，and instability index Ⅱ） were found to be most suitable for a drug target protein. Using the DrugBank database， seven compounds， namely Adenosine-5'-Rp-Alpha-Thio-Triphosphate， alpha，beta-Methyleneadenosine 5'-triphosphate， Phosphoaminophosphonic Acid-Adenylate Ester ，Radicicol，2-Hydroxyestradiol， p-Coumaric acid， and Ethylmercurithiosalicylic acid were identified as potential compounds capable of exerting anti-Nocardia effects by targeting this protein. Molecular docking results indicated a strong binding affinity between the target protein and these compounds. The experimental result showed that that Radicicol could be a potential antibacterial drug targeting this particular protein. ConclusionPan-genomic analysis and subtractive proteomics are valuable approaches for mining novel anti-Nocardia drug targets.

Establishment and application of detection methods of dicamba in drinking water / 环境与职业医学

Background Dicamba is widely used in agricultural production in China, but it is extremely soluble in water and can be harmful to human health when it enters the body via water drinking. It is necessary to establish an accurate, sensitive, and rapid detection method to determine the residues of dicamba in domestic drinking water. Objective To establish two methods for the determination of dicamba residues in drinking water by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS) respectively. Methods The conditions of the proposed method using HPLC-MS/MS included CAPCELL PAK ST chromatographic column, ammonium formate water solution and methanol as the mobile phase, and isocratic elution. The system was operated under multiple reaction monitoring mode and electrospray negative ionization mode. Trimethylsilylated diazomethane was used as a derivatizing agent for GC-MS/MS, and an external standard curve was used to evaluate the system. The residues of dicamba in seven water samples of tap water or secondary water supply from six regions in Chengdu were detected by the established systems to evaluate their applicability and to understand the status quo of dicamba residues in drinking water. Results For the HPLC-MS/MS, the linear range of dicamba was 1.00-100 μg·L−1, the regression equation was \begin{document}$\hat Y $\end{document}=1250.9X+2681.5, the correlation coefficient was 0.9988, the relative standard deviations were 1.23%-26.3%, the limit of detection was 0.95 μg·L−1, and the spiked recoveries were 91.8%-111%. For the GC-MS/MS, the linear range of dicamba was 0.200-10.0 μg·L−1, the regression equation was \begin{document}$\hat Y $\end{document}=190597X+40911, the correlation coefficient was 0.9993, the relative standard deviations were 0.64%-3.90%, the limit of detection was 0.18 μg·L−1, and the spiked recoveries were 97.3%-105%. No dicamba residue was identified in the seven water samples of tap water or secondary water supply from six regions in Chengdu by the proposed methods. Conclusion The two detection methods established in this study are sensitive and rapid, meet the requirements from the detection of dicamba residues in drinking water, and provide an experimental basis for subsequent research on the detection of dicamba residues. In the future, it is necessary to continue to pay attention to the pollution of dicamba in drinking water in Chengdu.

Evaluation of seasonal and monthly variation and location of deep vein thrombosis / Avaliação da variação sazonal e mensal e da localização da trombose venosa profunda

Abstract Background Deep vein thrombosis of the lower extremities is associated with a significant burden of comorbidities. Objectives In this study, our objective was to investigate the presence of seasonal variation in deep vein thrombosis (DVT) and assess the location of the thrombus. Methods Out of 8177 patients admitted to two university hospitals and referred to outpatient clinics, we included a total of 611 consecutive patients (316 females, 295 males) diagnosed with acute deep vein thrombosis in this retrospective study. The mean age of the patients was 59.35±18.49 years, ranging from 1 to 96 years. Patients were categorized into four groups by age. Results DVT was found to be more frequent in the summer (n = 190 or 31%, p = 0.003) and specifically in August (n = 65 or 10.6%, p = 0.014), while it was least frequent in the spring (n = 128 or 20.9%) and in May (n = 40 or 6.5%). However, when comparing seasons, no significant differences were observed in terms of seasonal variation (p = 0.062) or monthly variation (p = 0.143). Conclusions Contrary to previous studies, this study demonstrated a higher occurrence of DVT during the summer, particularly in August. However, it did not reveal a clear seasonal pattern. One plausible explanation for these findings could be the adverse winter conditions and transportation challenges within the province, which may result in fewer DVT patients being able to reach hospitals for timely treatment.

Resumo Contexto A trombose venosa profunda (TVP) dos membros inferiores está associada a uma carga significativa de comorbidades. Objetivos Investigar a presença de variação sazonal na TVP e identificar a localização do trombo. Métodos Dos 8.177 pacientes internados em dois hospitais universitários e encaminhados para ambulatórios, incluímos um total de 611 pacientes consecutivos (316 mulheres, 295 homens) diagnosticados com TVP aguda neste estudo retrospectivo. A idade média dos pacientes foi de 59,35±18,49 anos, variando de 1 a 96 anos. Os pacientes foram categorizados em quatro grupos com base na idade. Resultados A TVP foi mais frequente no verão (n = 190 ou 31%, p = 0,003), especificamente em agosto (n = 65 ou 10,6%, p = 0,014), e menos frequente na primavera (n = 128 ou 20,9%) e em maio (n = 40 ou 6,5%). No entanto, ao comparar as estações, não foram observadas diferenças significativas em termos de variação sazonal (p = 0,062) e variação mensal (p = 0,143). Conclusões Ao contrário de estudos anteriores, este estudo demonstrou maior ocorrência de TVP no verão, principalmente em agosto. No entanto, não revelou um padrão sazonal claro. Explicações plausíveis para essas descobertas seriam as condições adversas do inverno e dificuldades de deslocamento, o que pode resultar em menos pacientes com TVP chegando aos hospitais para tratamento oportuno.

Research progress of circadian rhythm and circadian clock gene regulation in the development of myopia / 国际眼科杂志(Guoji Yanke Zazhi)

With the development of society, the incidence of myopia and the population of myopia has increased year by year, which has become a major public health problem. Therefore, the research on the pathogenesis and prevention and control measures of myopia is imminent. In recent years, the role of the biological clock in the development of myopia has gradually attracted scholars interest. Now the author starts from the impact of the biological clock on the axial length, retina and choroid in the development of myopia. In order to provide new ideas for the study of prevention and control measures and the pathogenesis of myopia, a brief review is made from the perspective of contemporary society and disrupted body clock.