Insight into the Manipulation Mechanism of Polymorphic Transformation by Polymers: A Case of Cimetidine.

PURPOSE: Employing polymer additives is an effective strategy to realize the manipulation of polymorphic transformation. However, the manipulation mechanism is still not clear, which limit the precise selection of polymeric excipients and the development of pharmaceutical formulations. METHODS: The solubility of cimetidine (CIM) in acetonitrile/water mixtures were measured. And the polymorphic transformation from CIM form A to form B with the addition of different polymers was monitored by Raman spectroscopy. Furthermore, the manipulation effect of polymers was determined based on the results of experiments and molecular simulations. RESULTS: The solubility of form A is consistently higher than that of form B, which indicate that form B is the thermodynamically stable form within the examined temperature range. The presence of polyvinylpyrrolidone (PVP) of a shorter chain length could have a stronger inhibitory effect on the phase transformation process of metastable form, whereas polyethylene glycol (PEG) had almost no impact. The nucleation kinetics experiments and molecular dynamic simulation results showed that only PVP molecules could significantly decrease the nucleation rate of CIM, due to the ability of reducing solute molecular diffusion and solute-solute molecular interaction. A combination of crystal growth rate measurements and calculations of the interaction energies between PVP and the crystal faces of CIM indicate that smaller molecular weight PVP can suppress crystal growth more effectively. CONCLUSION: PVP K16-18 has more impact on the stabilization of CIM form A and inhibition of the phase transformation process. The manipulation mechanism of polymer additives in the polymorphic transformation of CIM was proposed.

Cardiovascular-specific mortality and risk factors in colorectal Cancer patients: A cohort study based on registry data of over 500,000 individuals in the US.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide, and recent studies have found that CRC patients are at increased risk for cardiovascular disease (CVD). This study aimed to investigate competing causes of death and prognostic factors among a large cohort of CRC patients and to describe cardiovascular-specific mortality in relation to the US standard population. METHODS: This registry-based cohort study identified patients diagnosed with CRC between 1973 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database in the US. Cumulative mortality functions, conditional standardized mortality ratios, and cause-specific hazard ratios were calculated. RESULTS: Of the 563,298 eligible CRC patients included in this study, 407,545 died during the follow-up period. CRC was the leading cause of death, accounting for 49.8% of all possible competing causes of death. CVD was the most common non-cancer cause of death, accounting for 17.8% of total mortality. This study found that CRC patients have a significantly increased risk of cardiovascular-specific mortality compared to the US standard population, with the risk increasing with age and extended survival time. CONCLUSION: This study highlights the need to develop multidisciplinary prevention and management strategies for CRC and CVD to improve CRC patients' survival and quality of life.

Polymorphism of Pradofloxacin: Crystal Structure Analysis, Stability Study, and Phase Transformation Behavior.

PURPOSE: Pradofloxacin is an important antibiotic with poor physical stability. At present, there is no systematic study on its polymorphic form. The purpose of this study is to develop new crystal forms to improve the stability of Pradofloxacin and systematically study the crystal transformation relationships to guide industrial production. METHOD: In this work, three solvent-free forms (Form A, Form B and Form C), a new dimethyl sulfoxide solvate (Form PL-DMSO) and a new hydrate (Form PL-H) were successfully obtained and the single crystal data of Form A, Form B and Form PL-DMSO were solved for the first time. Various solid state analysis techniques and slurry experiments have been used to evaluate the stability and determine phase transformation relationships of five crystal forms, the analysis of crystal structure provided theoretical support for the results. RESULT: The water vapor adsorption and desorption experiences of Forms A, B, C and Form PL-H were studied, and the results show that the new hydrate has good hygroscopic stability and certain development potential. The thermal stability of different forms was determined by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and the crystal structure shows that there are more hydrogen bonds and C - H···π interactions in form B, which is the reason why Form B is more stable than form A. Finally, the phase transformation relationships of the five crystal forms were systematically studied and discussed. CONCLUSION: These results are helpful to provide guiding methods in the production and storage of pradofloxacin.

Total arch replacement using a 4-branched vascular graft without circulatory arrest.

The technical essentials of the procedure include femoral artery cannulation, selective antegrade cerebral perfusion for brain protection, total arch replacement with a 4-branched vascular graft, implantation of the special open stented graft into the descending aorta, moderate hypothermic balloon occluding descending aorta at 25℃. This technique allows arch reconstruction to be debranched first and upper part of the body is perfused via the 4-branched vascular graft, ensuring antegrade true lumen cerebral perfusion rapidly secured, the descending aorta is arrested by balloon occluding and early rewarming and reperfusion after distal anastomosis to minimize organs ischemia.

Trimodal operation of a robust smart organic crystal.

We describe a dynamic crystalline material that integrates mechanical, thermal, and light modes of operation, with unusual robustness and resilience and a variety of both slow and fast kinematic effects that occur on very different time scales. In the mechanical mode of operation, crystals of this material are amenable to elastic deformation, and they can be reversibly morphed and even closed into a loop, sustaining strains of up to about 2.6%. Upon release of the external force, the crystals resume their original shape without any sign of damage, demonstrating outstanding elasticity. Application of torque results in plastic twisting for several rotations without damage, and the twisted crystal can still be bent elastically. The thermal mode of operation relies on switching the lattice at least several dozen times. The migration of the phase boundaries depends on the crystal habit. It can be precisely controlled by temperature, and it is accompanied by both slow and fast motions, including shear deformation and leaping. Parallel boundaries result in a thermomechanical effect, while non-parallel boundaries result in a thermosalient effect. Finally, the photochemical mode of operation is driven by isomerization and can be thermally reverted. The structure of the crystal can also be switched photochemically, and the generation of a bilayer induces rapid bending upon exposure to ultraviolet light, an effect that further diversifies the mechanical response of the material. The small structural changes, low-energy and weak intramolecular hydrogen bonds, and shear deformation, which could dissipate part of the elastic energy, are considered to be the decisive factors for the conservation of the long-range order and the extraordinary diversity in the response of this, and potentially many other dynamic crystalline materials.

Clinical Application of Proximal Arch Cannulation in the Surgical Treatment of Acute Type I Aortic Dissection.

Objective The goal is to determine the best location for inserting a catheter into the aortic arch of patients with a certain type of aortic dissection (DeBakey type I) by analyzing images of the patient's aortic arch before surgery. This analysis will take into account the shape and structure of the patient's aortic arch to find the most optimal location for cannulation. Methods A retrospective analysis was conducted on 100 patients with acute DeBakey type I aortic dissection diagnosed between January 2021 and February 2023, utilizing the Carestream medical imaging software Image Suite V4 (New York, USA). The study included 67 cases that underwent surgery and 33 cases that did not. The study aimed to evaluate the optimal intubation position on the patient's aortic arch by analyzing the true and false lumen classification, true and false lumen area, and hematoma thickness on the patient's aortic arch, as observed in the aortic computed tomography angiography (CTA) conducted upon admission. Results The vascular axis analysis showed a significant difference in the true lumen area among the three regions that were examined (P < 0.001). Zone 1 had a larger true lumen area of 6.40 ± 2.71 cm2 compared to zone 2 with 5.75 ± 2.13 cm2 and zone 3 with 4.85 ± 1.70 cm2, as determined by statistical analysis. In addition, the statistical analysis of hematoma thickness in the three regions where cannulation can be performed revealed a significant difference among the three groups (P = 0.027). Further analysis showed that there was no significant difference between zone 1 and zone 2 (P = 1.000), a significant difference between zone 1 and zone 3 (P < 0.046), and no significant difference between zone 2 and zone 3 (P = 0.080). The difference between zone 1 false lumen thickness of 1.55 ± 0.51 cm and zone 3 false lumen thickness of 1.33 ± 0.55 cm was found to be small. Conclusion Cannulation of the aortic arch is a common strategy used in cardiac surgery. Accurate cannulation is critical to the success of the procedure. The use of CTA provides valuable guidance for the cannulation procedure. A thorough examination of CTA and precise measurement of relevant parameters can help guide the surgeon to determine the optimal cannulation site. The study found that zone 1 of the aortic arch has the largest area and is the most suitable for cannulation, in accordance with the physiological characteristics and surgical practices of a surgeon. Furthermore, cannulation of the aortic arch has been found to be a safe and effective strategy for cannulation. Overall, careful examination of CTA and accurate measurement of relevant parameters can have a significant guiding effect on the cannulation of the aortic arch, which can lead to improved outcomes in cardiac surgery.

ASIC1/RIP1 accelerates atherosclerosis via disrupting lipophagy.

INTRODUCTION: Atherosclerosis, a major contributor to cardiovascular disease, remains a significant health concern worldwide. While previous research has shown that acid-sensing ion channel 1 (ASIC1) impedes macrophage cholesterol efflux, its precise role in atherogenesis and the underlying mechanisms have remained elusive. OBJECTIVES: This study aimed to investigate the role of ASIC1 in atherosclerosis and its underlying mechanisms. METHODS: First, data from a single-cell RNA sequencing (scRNA-seq) database were used to explore the relationships between ASIC1 differential expression and lipophagy in human atherosclerotic lesions. Finally, we validated the role of ASIC1/RIP1 signaling in lipophagy in vivo (human and mice) and in vitro (RAW264.7 and HTP-1 cells). RESULT: Our results demonstrated a significant increase in ASIC1 protein levels within CD68+ macrophages in both human aortic lesions and AopE-/- mouse lesion areas compared to nonlesion regions. Concurrently, there was a notable decrease in lipophagy, a crucial process for lipid metabolism. In vitro assays further elucidated that ASIC1 interaction with RIP1 (receptor-interacting protein 1) promoted the phosphorylation of RIP1 at serine 166 and transcription factor EB (TFEB) at serine 142, leading to disrupted lipophagy and increased lipid accumulation. Intriguingly, all these events were reversed upon ASIC1 deficiency and RIP1 inhibition. Furthermore, in ApoE-/- mouse models of atherosclerosis, silencing ASIC1 expression or inhibiting RIP1 activation not only significantly attenuated atherogenesis but also restored TFEB-mediated lipophagy in aortic tissues. This was evidenced by reduced TFEB Ser-142 phosphorylation, decreased LC3II and LAMP1 protein expression, increased numbers of lipophagosomes, and a decrease in lipid droplets. CONCLUSION: Our findings unveil the critical role of macrophage ASIC1 in interacting with RIP1 to inhibit lipophagy, thereby promoting atherogenesis. Targeting ASIC1 represents a promising therapeutic avenue for the treatment of atherosclerosis.

Myocardin suppression increases lipid retention and atherosclerosis via downregulation of ABCA1 in vascular smooth muscle cells.

Myocardin (MYOCD) plays an important role in cardiovascular disease. However, its underlying impact on atherosclerosis remains to be elucidated. ATP binding cassette transporter A1 (ABCA1), a key membrane-associated lipid transporter which maintains intracellular lipid homeostasis, has a protective function in atherosclerosis progress. The purpose of this study was to investigate whether and how the effect of MYOCD on atherosclerosis is associated with ABCA1 in vascular smooth muscle cells (VSMCs). We found both MYOCD and ABCA1 expression were dramatically decreased in atherosclerotic patient aortas compared to control. MYOCD knockdown inhibited ABCA1 expression in human aortic vascular smooth muscle cells (HAVSMCs), leading to reduced cholesterol efflux and increased intracellular cholesterol contents. MYOCD overexpression exerted the opposite effect. Mechanistically, MYOCD regulates ABCA1 expression in an SRF-dependent manner. Consistently, apolipoprotein E-deficient mice treated with MYOCD shRNA developed more plaques in the aortic sinus, which is associated with reduced ABCA1 expression, increased cholesterol retention in the aorta, and decreased high-density lipoprotein cholesterol levels in the plasma. Our data suggest that MYOCD deficiency exacerbates atherosclerosis by downregulating ABCA1 dependent cholesterol efflux from VSMCs, thereby providing a novel strategy for the therapeutic treatment of atherosclerotic cardiovascular disease.

[Bovine jugular venous conduit treated with the polyepoxy compound].

OBJECTIVE: To determine the feasibility whether the bovine jugular venous conduit (BJVC) can be fixed with polyepoxy compound (PC). METHODS: Twenty-four BJVCs were divided into 3 groups and fixed with polyepoxy compound (PC group, n = 8), glutaraldehyde (GA group, n = 8), and unfixed group (Control group, n = 8), respectively. The morphologic and mechanical properties of BJVCs in the 3 groups, including thickness, diameter, moisture content, denaturation temperature, tensile strength, elongation at break, and fixation index were measured. The rat subcutaneous model for the assessment of tissue calcification was used. The calcium content in bovine jugular vein patches and valves was determined by flame atomic absorption spectrophotometer. RESULTS: There was no difference in the wall thickness, diameter, and tissue water content between PC and the control group, but significant difference was found between GA and PC groups. The mechanical properties of PC group and GA group were not significantly different, but they were better than those of the control group. GA-fixed BJVC samples showed clear calcification, while PC fixed BJVC were calcified significantly less. CONCLUSION: PC is an effective and suitable choice for the treatment of BJVC since it can effectively preserve the structure and the anti-reflow function of valves in bovine jugular vein and it has better anti-calcification properties.

[Immunogenicity of bovine jugular vein conduits treated with different cross-linking methods].

OBJECTIVE: To evaluate the immunogenicity of bovine jugular vein conduits (BJVCs) treated with different cross-linking methods. METHODS: The BJVCs were treated with glutaradehyde (GA), dye-mediated photooxidation (DMP) and polyepoxy compound (PC) (n = 10). The tissue homogenates obtained from BJVCs treated with PC, GA, DMP, and fresh BJVCs, were mixed with the complete Freand adjavant to form the emulsive antigen, which were used to immunize rabbits correspondently. The antibody concentrations to BJVCs in those rabbits' serum were measured by counter double immuno diffusion. The immunologic responses to the BJVCs in different groups were measured with Western blotting. RESULTS: The positive bands appeared when the sera of rabbits were immunized by fresh BJVCs reacted with antigens of fresh BJVCs, but no bands appeared when the sera of rabbits were immunized by fresh BJVCs reacted with those antigens of the BJVCs treated with GA, DMP, and PC in Western blotting. CONCLUSION: The immunogenicity of BJVCs treated with PC, DMP, and GA can be reduced significantly and meet the clinical standard.

[Myocardial protective effects of pretreatment with captopril on ischemia-reperfusion myocardium in rabbits].

OBJECTIVE: To investigate the effect of pretreatment with captopril on myocardium ischemia-reperfusion injury in atherosclerotic rabbits. METHODS: Thirty-two New Zealand white rabbits were assigned randomly to the normally feed group, cholesterol-feed (CF) group, and cholesterol food plus captopril group (cap-feed group), which were fed for 10 weeks. We examined the changes in the size of the infarct and changes in the myocardium ultrastructure resulting from coronary ischemia/reperfusion. Levels of endothelin (ET) and nitic oxide (NO) were measured in the different experiment stages. RESULTS: The ET levels significantly increased and the content of NO significantly decreased in the CF group compared with those of the cap-feed group. The ultrastructure of myocardium cell was slightly destroyed and the infarct size was significantly smaller in the cap-feed group than the normally feed rabbits and CF rabbits. CONCLUSION: The long-term captopril treatment can lighten the severity of myocardial injury produced by coronary ischemia/reperfusion.

[Morphologic and physiochemical properties of bovine jugular conduit stabilized by dye-mediated poto-oxidation].

OBJECTIVE: To determine the morphologic and physiochemical properties of bovine jugular conduit with valves stabilized by dye-mediated photo-oxidation. METHODS: Twenty-four bovine jugular conduits with valves were divided into 3 groups and treated with dye-mediated photo-oxidation (Group I), glutaraldehyde (Group II) and untreated group (Group II), respectively. Morphologic and physiochemical properties of the 3 groups, including wall thickness, diameter, tissue water content, heat shrinking temperature, breaching strength, and tissue protein extraction assay were studied. RESULTS: There was no difference in wall thickness, diameter, tissue water content, and heat shrinking temperature between Group I and II ,but there was significant difference between Group I and II. The breaching strength of Group I was higher than that of Group IU (P < 0.05), but lower than that of Group II (P < 0. 05). A decrease in extractable tissue protein was found in Group I and II. CONCLUSION: The dye-mediated photooxidation can effectively preserve the structure and the anti-regurgitation function of valves and improve the tissue stability and enhance the tension of bovine jugular conduit with valves.