Diabetes and aortic dissection: unraveling the role of 3-hydroxybutyrate through mendelian randomization.

BACKGROUND: In observational and experimental studies, diabetes has been reported as a protective factor for aortic dissection. 3-Hydroxybutyrate, a key constituent of ketone bodies, has been found to favor improvements in cardiovascular disease. However, whether the protective effect of diabetes on aortic dissection is mediated by 3-hydroxybutyrate is unclear. We aimed to investigate the causal effects of diabetes on the risk of aortic dissection and the mediating role of 3-hydroxybutyrate in them through two-step Mendelian randomization. MATERIALS AND METHODS: We performed a two-step Mendelian randomization to investigate the causal connections between diabetes, 3-hydroxybutyrate, and aortic dissection and calculate the mediating effect of 3-hydroxybutyrate. Publicly accessible data for Type 1 diabetes, Type 2 diabetes, dissection of aorta and 3-hydroxybutyrate were obtained from genome-wide association studies. The association between Type 1 diabetes and dissection of aorta, the association between Type 2 diabetes and dissection of aorta, and mediation effect of 3-hydroxybutyrate were carried out separately. RESULTS: The IVW method showed that Type 1 diabetes was negatively associated with the risk of aortic dissection (OR 0.912, 95% CI 0.836-0.995), The weighted median, simple mode and weighted mode method showed consistent results. The mediated proportion of 3-hydroxybutyrate on the relationship between Type 1 diabetes and dissection of aorta was 24.80% (95% CI 5.12-44.47%). The IVW method showed that Type 2 diabetes was negatively associated with the risk of aortic dissection (OR 0.763, 95% CI 0.607-0.960), The weighted median, simple mode and weighted mode method showed consistent results. 3-Hydroxybutyrate does not have causal mediation effect on the relationship between Type 2 diabetes and dissection of aorta. CONCLUSION: Mendelian randomization study revealed diabetes as a protective factor for dissection of aorta. The protective effect of type 1 diabetes on aortic dissection was partially mediated by 3-hydroxybutyrate, but type 2 diabetes was not 3-hydroxybutyrate mediated.

Sensorineural hearing loss induced by gefitinib: A CARE-compliant case report and literature reviews.

RATIONALE: Gefitinib is a potent and selective orally active growth factor receptor (EGFR)-tyrosine kinase inhibitor that is commonly used to treat advanced non-small cell lung cancer patients with activating EGFR mutations. Hearing impairment with gefitinib was sparsely reported. In this report, we describe a case of sensorineural deafness associated with the administration of gefitinib, with a Naranjo score of 7. PATIENT CONCERNS: An 81-year-old female was diagnosed with lung adenocarcinoma with bone metastasis and an EGFR-activating mutation. The patient was prescribed gefitinib tablets at a daily dose of 250 mg for lung adenocarcinoma treatment. However, the patient experienced moderate to severe bilateral sensorineural deafness, primarily in her right ear, after taking gefitinib. Following the cessation of gefitinib administration, the patient exhibited partial restoration of auditory function. Upon resuming the medication, she experienced a worsening of deafness. DIAGNOSES: The otoscopic audiogram and hearing test indicated moderate to severe bilateral sensorineural deafness. INTERVENTIONS: The otolaryngologist recommended bilateral hearing aids to enhance hearing function. OUTCOMES: Throughout our follow-up period, the patient did not receive a hearing aid implant. LESSONS: This article first reported the ototoxicity caused by gefitinib. While rare, our report highlights that gefitinib-induced sensorineural deafness is possible and its mechanisms are still unclear. This adverse reaction should be monitored closely during clinical application of gefitinib to improve patient outcomes.

Surface Modification and Functionalities for Titanium Dental Implants.

Dental implants have become the mainstream strategy for oral restoration, and implant materials are the most important research hot spot in this field. So far, Ti implants dominate all kinds of implants. The surface properties of the Ti implant play decisive roles in osseointegration and antibacterial performance. Surface modifications can significantly change the surface micro/nanotopography and composition of Ti implants, which will effectively improve their hydrophilicity, mechanical properties, osseointegration performance, antibacterial performance, etc. These optimizations will thus improve implant success and service life. In this paper, the latest surface modification techniques of Ti dental implants are systematically and comprehensively reviewed. The various biomedical functionalities of surface modifications are discussed in-depth. Finally, a profound comment on the challenges and opportunities of this frontier is proposed, and the most promising directions for the future were explored.

Suppressing high mobility group box-1 release alleviates morphine tolerance via the adenosine 5'-monophosphate-activated protein kinase/heme oxygenase-1 pathway.

Opioids, such as morphine, are the most potent drugs used to treat pain. Long-term use results in high tolerance to morphine. High mobility group box-1 (HMGB1) has been shown to participate in neuropathic or inflammatory pain, but its role in morphine tolerance is unclear. In this study, we established rat and mouse models of morphine tolerance by intrathecal injection of morphine for 7 consecutive days. We found that morphine induced rat spinal cord neurons to release a large amount of HMGB1. HMGB1 regulated nuclear factor κB p65 phosphorylation and interleukin-1ß production by increasing Toll-like receptor 4 receptor expression in microglia, thereby inducing morphine tolerance. Glycyrrhizin, an HMGB1 inhibitor, markedly attenuated chronic morphine tolerance in the mouse model. Finally, compound C (adenosine 5'-monophosphate-activated protein kinase inhibitor) and zinc protoporphyrin (heme oxygenase-1 inhibitor) alleviated the morphine-induced release of HMGB1 and reduced nuclear factor κB p65 phosphorylation and interleukin-1ß production in a mouse model of morphine tolerance and an SH-SY5Y cell model of morphine tolerance, and alleviated morphine tolerance in the mouse model. These findings suggest that morphine induces HMGB1 release via the adenosine 5'-monophosphate-activated protein kinase/heme oxygenase-1 signaling pathway, and that inhibiting this signaling pathway can effectively reduce morphine tolerance.

ß-sheets in serum protein are independent risk factors for coronary lesions besides LDL-C in coronary heart disease patients.

Background: Coronary heart disease (CHD) patients with standard low-density lipoprotein cholesterol (LDL-C) remain at risk of cardiovascular events, making it critical to explore new targets to reduce the residual risk. The relationship between ß-sheet conformation and CHD is gaining attention. This study was designed to compare the coronary lesions in CHD patients with varying LDL-C and evaluate whether serum ß-sheets are associated with coronary damage. Methods: Two hundred and one patients diagnosed with stable CHD were recruited and divided into four groups according to LDL-C. Baseline information, coronary lesion-related indicators, and peripheral blood samples were collected. Serum ß-sheet content was determined by thioflavin T fluorescence. Results: The baseline information was comparable in CHD patients with different LDL-C. No difference was found in indicators relevant to coronary lesions among groups. The content of ß-sheet was negatively correlated with LDL-C. Multiple linear regression revealed that serum ß-sheet was positively correlated with coronary lesion when risk factors such as age, smoking, and LDL-C were controlled. Conclusions: This is the first study that reports the serum ß-sheet levels of CHD patients being gradually increased with decreasing LDL-C when coronary lesions were comparable. Serum ß-sheet might exacerbate the coronary lesions in CHD patients independent of known risk factors such as LDL-C.

Endothelial microparticle-associated protein disulfide isomerase increases platelet activation in diabetic coronary heart disease.

BACKGROUND: Endothelial microparticles (EMPs) carrying the protein disulfide isomerase (PDI) might play a key role in promoting platelet activation in diabetes. This study aimed to examine the activation of platelets, the amounts of MPs, PMPs, and EMPs, and the concentration and activity of PDI in patients with diabetic coronary heart disease (CHD) and non-diabetic CHD. METHODS: Patients with CHD (n=223) were divided as non-diabetic CHD (n=121) and diabetic CHD (n=102). Platelet activation biomarkers, circulating microparticles (MPs), the concentration of protein disulfide isomerase (PDI), and MP-PDI activity were determined. The effect of EMPs on platelet activation was investigated in vitro. Allosteric GIIb/IIIa receptors that bind to PDI were detected by a proximity ligation assay (PLA). RESULTS: Platelet activation, platelet-leukocyte aggregates, circulating MPs, EMPs, PDI, and MP-PDI activity in the diabetic CHD group were significantly higher than in the non-diabetic CHD group (P<0.05). Diabetes (P=0.006) and heart rate <60 bpm (P=0.047) were associated with elevated EMPs. EMPs from diabetes increased CD62p on the surface of the platelets compared with the controls (P<0.01), which could be inhibited by the PDI inhibitor RL90 (P<0.05). PLA detected the allosteric GIIb/IIIa receptors caused by EMP-PDI, which was also inhibited by RL90. CONCLUSIONS: In diabetic patients with CHD, platelet activation was significantly high. Diabetes and heart rate <60 bpm were associated with elevated EMPs and simultaneously increased PDI activity on EMP, activating platelets through the allosteric GPIIb/IIIa receptors.

Ti3C2Txnanohybrids: tunable local conductive network and efficient EMI shielding performance for multifunctional materials and devices.

Ti3C2Txis an important member of the MXenes family. Due to its excellent electrical conductivity, adjustable atomic layer, and modifiable active surface, Ti3C2Txhas attracted great attention in the field of electromagnetic interference (EMI) shielding. This paper introduces the important role of regulating conductive network to improve the EMI shielding performance of materials and summarizes the EMI shielding performance of Ti3C2Txnanohybrids reported in recent years. In addition, Ti3C2Txbased EMI shielding materials towards multifunctional devices are also systematically introduced. After that, the development status of Ti3C2Txnanohybrids in the field of EMI shielding is objectively described, and the main problems and challenges are evaluated. Finally, the prospect of Ti3C2Txnanohybrids for advanced and green EMI shielding materials is forecasted.

Morphine induces dysfunction of PINK1/Parkin-mediated mitophagy in spinal cord neurons implying involvement in antinociceptive tolerance.

The development of opioid-induced analgesic tolerance is a clinical challenge in long-term use for managing chronic pain. The mechanisms of morphine tolerance are poorly understood. Mitochondria-derived reactive oxygen species (ROS) is a crucial signal inducing analgesic tolerance and pain. Chronic administration of morphine leads to robust ROS production and accumulation of damaged mitochondria, which are immediately removed by mitophagy. Here, we show that morphine inhibits mitochondria damage-induced accumulation of PTEN-induced putative kinase 1 (PINK1) in neurons. It interrupts the recruitment of Parkin to the impaired mitochondria and inhibits the ubiquitination of mitochondrial proteins catalyzed by Parkin. Consequently, morphine suppresses the recognition of autophagosomes to the damaged mitochondria mediated by LC3 and sequestosome-1 (SQSTM1/p62). Thus, morphine inhibits autophagy flux and leads to the accumulation of SQSTM1/p62. Finally, the impaired mitochondria cannot be delivered to lysosomes for degradation and ultimately induces robust ROS production and morphine tolerance. Our findings suggest that the dysfunction of mitophagy is involved in morphine tolerance. The deficiency of PINK1/Parkin-mediated clearance of damaged mitochondria is crucial for the generation of excessive ROS and important to the development of analgesic tolerance. These findings suggest that the compounds capable of stabilizing PINK1 or restoring mitophagy may be utilized to prevent or reduce opioid tolerance during chronic pain management.

[Effects of gabapentin on high-voltage-activated calcium current in dorsal root ganglion neurons in rats].

OBJECTIVE: To compare the effects of gabapentin on high-voltage-activated calcium (HVA) current in dorsal root ganglion (DRG) neurons in normal and nerve-injured rats and understand the reasons of their differences. METHODS: Pathogen-free male SD rats (weight 180 - 220 mg) aged 4 - 6 weeks were used. The animals were anesthetized with intraperitoneal pentobarbital sodium 50 mg/kg. L(5) spinal nerve was ligated between DRG and sciatic nerve and cut distal to the ligature. The animals were decapitated at Day 14 post-operation. L(5) (SNL-L(5) group) and L(4) DRGs (SNL-L(4) group) were respectively isolated and the ganglionic neurons enzymatically dissociated. The control group of rats was not operated. The lumbar DRG neurons of normal rats were treated similarly. The HVA-Ca(2+) current was recorded by the technique of whole cell patch clamp. RESULTS: Compared with the SNL-L(4) group [(16.0 ± 1.9)%, (26.9 ± 2.0)%, (27.4 ± 2.3)%] and the control group, gabapentin inhibited the peak calcium current highlier at 10, 100 and 300 µmol/L in the SNL-L(5) group [(18.5 ± 1.7)%, (32.0 ± 2.6)%, (32.7 ± 2.8)%] (P < 0.05). The steady-state inactivation curves shifted to more hyperpolarized potentials in the SNL-L(5) group. The N-type relative contribution to the gabapentin-sensitive HVA-Ca(2+) current was markedly elevated in the SNL-L(5) group compared with that in other two groups (P < 0.05). CONCLUSION: Gabapentin enhances the inhibition of HVA-Ca(2+) current in injured DRG neurons following spinal nerve ligation in rats. The alteration in the activation of electrophysiological properties and the increase of N-type relative contribution to the total HVA-Ca(2+) current may be involved in the mechanism.

[Effects of deer tendons collagen on osteoporosis rats induced by retinoic acid].

OBJECTIVE: To study the effects of deer tendons collagen on osteoporosis rats induced by retinoic acid. METHODS: Male Wistar rats were randomly divided into normal control group, model control group, deer tendons collagen high, medium and low-dose groups, osteoporosis rats of retinoic acid-induced were set up. Changes of body weight, bone weight, bone mineral density, bone histomorphometry, plasma phosphorus, calcium, alkaline phosphatase (ALP), bone mechanics were measured before and after treatment of deer tendons collagen. RESULTS: Compared with model control group,after treated by deer tendons collagen, body weight, bone mineral density, bone weight was increased in varying degrees, bone histomorphometry parameters were significantly different, the ALP in plasma was significantly reduced, contents of Ca, P were increased, all indicators of bone mechanics were significantly higher. CONCLUSION: Deer tendons collagen can prevent and treat retinoic acid-induced osteoporosis of rats.

[Clinical observation of effect of jiawei yupingfeng mixture for prevention and treatment of 100 children with repeated respiratory tract infection].

OBJECTIVE: To investigate the effect of Jiawei Yupingfeng Mixture (YPF) on repeated respiratory tract infection (RRTI) and its impacts on T-cell subsets, immunoglobulin and erythrocyte immune. METHODS: Two hundred children with RRTI were assigned equally to two groups, the test group treated with YPF and the control group treated by transfer factor. The clinical efficacy, and the changes of T-cell subsets, immunoglobulin and erythrocyte immune before and after treatment were observed in 31 patients randomly selected from each group. RESULTS: After treatment, the frequency of attacking was reduced and the course of attacking was shortened significantly in the test group as compared with before treatment and also with the control group (P < 0.01); IgG and IgA levels were improved in both groups, but the improvement was more significant in the test group (P<0.01, P<0.05); T-cell subsets indices, including CD3(+), CD4(+), CD8(+) and CD4(+)/CD8(+) ratio, all improved in the test group significantly (P <0.01), while in the control group, significant improvement only showed in rising of CD3(+) and CD4(+) (P <0.05, P <0.01), comparison between groups showed significant difference in terms of CD3(+), CD4(+) and CD8(+); in the control group, levels of C3b, RFER and RFIR were changed significantly (P<0.05, P<0.01), but the improvement of ICR was insignificant, while in the test group, the above indices were significant improved as compared with after treatment of the control group (P <0.01). CONCLUSION: YPF plays a preventive and therapeutic role in children with RRTI by way of regulating the cellular and humoral immune.

[Analysis of the curriculum of the University of California, Los Angeles School of Dentistry].

By comparative analysis of the curriculum of the University of California, Los Angeles (UCLA) School of Dentistry with Shandong University College of Stomatology, this paper explored what could be used as reference for Chinese dental educators. The curriculum characteristics and teaching ways in UCLA was analyzed; the dental courses of UCLA were compared with Shandong University, fourteen courses opened in UCLA were not opened in Shandong University; eight forefront courses selected from the fourteen courses were introduced. The analysis showed that in certain degree the curriculum characteristics and teaching ways of UCLA could be used for reference and fourteen forefront courses were also necessary. It's suggested to increase the proportion of dental courses, increase hours for experiments, combine theories and experiments tightly and gradually open forefront courses such as Clinical Applications of Dental Morphology, Esthetic Dentistry, Geriatric Dentistry, Hospital Dentistry, Health Policy Issues, Methods in Evidence-based Dentistry, Introduction to Behavioral Science, Patient Management and so on within domestic universities.