The investigation of thrombocytopenia after transcatheter occlusion of patent ductus arteriosus.

OBJECTIVE: To investigate the risk factors for thrombocytopenia after transcatheter occlusion operation of patent ductus arteriosus (PDA). METHOD: Retrospective analyses were conducted using clinical data from 106 patients with PDA who underwent transcatheter closure operations at Henan Provincial Chest Hospital, Zhengzhou University, from January 2018 to June 2022. The study compared the changes in platelet counts before and after the operation, and investigated the risk factors for thrombocytopenia following PDA closure in different groups and layers. RESULTS: The platelet count of patients with PDA significantly decreased after undergoing transcatheter PDA occlusion. Logistic regression analysis revealed that factors such as PDA diameter, occluder diameter, pressure difference on the two sides of the occluder, and residual shunt were associated with an increased risk of thrombocytopenia following PDA occlusion. Specifically, the size of the occluder and the pressure difference between the two sides of the occluder were found to have a negative correlation with the postoperative platelet count. Further subgroup analysis demonstrated that the incidence of total thrombocytopenia was significantly higher in the large PDA group compared to the small-medium PDA groups. CONCLUSION: Our findings suggest that occluder diameter, the pressure difference between the two sides of the occluder, and the residual shunt are major risk factors correlated with the incidence of postoperative thrombocytopenia. However, a multicenter and long-term prospective study is required to further evaluate the prognosis of PDA patients with thrombocytopenia after transcatheter occlusion.

Ketogenic diet inhibits neointimal hyperplasia by suppressing oxidative stress and inflammation.

OBJECTIVE: Neointimal hyperplasia is the primary mechanism underlying atherosclerosis and restenosis after percutaneous coronary intervention. Ketogenic diet (KD) exerts beneficial effects in various diseases, but whether it could serve as non-drug therapy for neointimal hyperplasia remains unknown. This study aimed to investigate the effect of KD on neointimal hyperplasia and the potential mechanisms. METHODS AND RESULTS: Carotid artery balloon-injury model was employed in adult Sprague-Dawley rats to induce neointimal hyperplasia. Then, animals were subjected to either standard rodent chow or KD. For in-vitro experiment, impacts of ß-hydroxybutyrate (ß-HB), the main mediator of KD effects, on platelet-derived growth factor BB (PDGF-BB) induced vascular smooth muscle cell (VSMC) migration and proliferation were determined. Balloon injury induced event intimal hyperplasia and upregulation of protein expression of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA), and these changes were significantly ameliorated by KD. In addition, ß-HB could markedly inhibit PDGF-BB induced VMSC migration and proliferation, as well as inhibiting expressions of PCNA and α-SMC. Furthermore, KD inhibited balloon-injury induced oxidative stress in carotid artery, indicated by reduced ROS level, malondialdehyde (MDA) and myeloperoxidase (MPO) activities, and increased superoxide dismutase (SOD) activity. We also found balloon-injury induced inflammation in carotid artery was suppressed by KD, indicated by decreased expressions of proinflammatory cytokines IL-1ß and TNF-α, and increased expression of anti-inflammatory cytokine IL-10. CONCLUSION: KD attenuates neointimal hyperplasia through suppressing oxidative stress and inflammation to inhibit VSMC proliferation and migration. KD may represent a promising non-drug therapy for neointimal hyperplasia associated diseases.

Translating cancer genomics into precision medicine with artificial intelligence: applications, challenges and future perspectives.

In the field of cancer genomics, the broad availability of genetic information offered by next-generation sequencing technologies and rapid growth in biomedical publication has led to the advent of the big-data era. Integration of artificial intelligence (AI) approaches such as machine learning, deep learning, and natural language processing (NLP) to tackle the challenges of scalability and high dimensionality of data and to transform big data into clinically actionable knowledge is expanding and becoming the foundation of precision medicine. In this paper, we review the current status and future directions of AI application in cancer genomics within the context of workflows to integrate genomic analysis for precision cancer care. The existing solutions of AI and their limitations in cancer genetic testing and diagnostics such as variant calling and interpretation are critically analyzed. Publicly available tools or algorithms for key NLP technologies in the literature mining for evidence-based clinical recommendations are reviewed and compared. In addition, the present paper highlights the challenges to AI adoption in digital healthcare with regard to data requirements, algorithmic transparency, reproducibility, and real-world assessment, and discusses the importance of preparing patients and physicians for modern digitized healthcare. We believe that AI will remain the main driver to healthcare transformation toward precision medicine, yet the unprecedented challenges posed should be addressed to ensure safety and beneficial impact to healthcare.

[Astragaloside IV inhibits oxidative stress-mediated apoptosis of human SY5Y cells by activating Nrf-2/HO-1 signaling pathway].

Objective To investigate the protective effect and mechanism of astragaloside IV (AST4) on H2O2-induced oxidative stress injury and apoptosis of SY5Y cells. Methods Human SY5Y cells were cultured in vitro and induced by H2O2 to establish oxidative stress model, which was divided into PBS group, H2O2 group and AST4 group. Cell viability was determined by MTT assay. Cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL). The supernatant was used to determine the activity of malondialdehyde (MAD), superoxide dismutase (SOD) and glutathione (GSH) in each group. Immunofluorescence cytochemistry was used to detect the nuclear factor E2-related factor (Nrf-2) and cleaved caspase-3 (c-caspase-3). B-lymphoblastoma-2 (Bcl2), Bcl2-associated X protein (BAX), c-caspase-3, Nrf-2 in cells and nuclei and heme oxygenase-1 (HO-1) were determined by Western blot analysis. Results AST4 had a protective effect on viability of SY5Y cells under oxidative stress damage, reduced the content of MAD, and increased the content of GSH and SOD. AST4 increased Bcl2 and decreased BAX, thus Bc12/BAX ratio was significantly increased compared with that in H2O2 group. Meanwhile, AST4 inhibited the expression of c-caspase-3. AST4 promoted nuclear translocation of Nrf-2 and increased the expression of the downstream antioxidant protein HO-1. Conclusion AST4 can promote Nrf-2 nuclear translocation, increase HO-1 expression, regulate oxidation/antioxidant balance, improve antioxidant level, protect cells from oxidative damage and reduce apoptosis by activating Nrf-2/HO-1 signaling pathway.

Diagnostic values of Xpert MTB/RIF, T-SPOT.TB and adenosine deaminase for HIV-negative tuberculous pericarditis in a high burden setting: a prospective observational study.

The diagnosis of tuberculous pericarditis (TBP) remains challenging. This prospective study evaluated the diagnostic value of Xpert MTB/RIF (Xpert) and T-SPOT.TB and adenosine deaminase (ADA) for TBP in a high burden setting. A total of 123 HIV-negative patients with suspected TBP were enrolled at a tertiary referral hospital in China. Pericardial fluids were collected and subjected to the three rapid tests, and the results were compared with the final confirmed diagnosis. Of 105 patients in the final analysis, 39 (37.1%) were microbiologically, histopathologically or clinically diagnosed with TBP. The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio (DOR) for Xpert were 66.7%, 98.5%, 96.3%, 83.3%, 44.0, 0.338, and 130.0, respectively, compared to 92.3%, 87.9%, 81.8%, 95.1%, 7.6, 0.088, and 87.0, respectively, for T-SPOT.TB, and 82.1%, 92.4%, 86.5%, 89.7%, 10.8, 0.194, and 55.8, respectively, for ADA (≥ 40 U/L). ROC curve analysis revealed a cut-off point of 48.5 spot-forming cells per million pericardial effusion mononuclear cells for T-SPOT.TB, which had a DOR value of 183.8, while a cut-off point of 41.5 U/L for ADA had a DOR value of 70.9. Xpert (Step 1: rule-in) followed by T-SPOT.TB [cut-off point] (Step 2: rule-out) showed the highest DOR value of 252.0, with only 5.7% (6/105) of patients misdiagnosed. The two-step algorithm consisting of Xpert and T-SPOT.TB could offer rapid and accurate diagnosis of TBP.

Effects of Bi2O3 Doping on the Mechanical Properties of PbO Ceramic Pellets Used in Lead-Cooled Fast Reactors.

In this paper, the effects of Bi2O3 doping on the mechanical properties of PbO ceramic pellets were studied. Different ratios of Bi2O3/PbO (i.e., xBi2O3-(1-x) PbO, where x is 0, 1, 3, 5, or 7 wt.%) were fabricated and sintered at 570, 620, and 670 °C. Mechanical properties including density, hardness, flexural strength, and sintering of PbO were studied for each of the aforementioned compositions. Phase composition, microstructure, and the worn surfaces of the composites were characterized by scanning electron microscopy and X-ray diffraction (XRD). The XRD analysis revealed that a solid solution formed in the composite ceramic. The best suited conditions of temperature and doping of Bi2O3 for optimal sintering were found to be 620 °C and 3 wt.%, respectively. The hardness of the 3 wt.% Bi2O3-97 wt.% PbO ceramic was found to be 717 MPa, which is about four times higher than the hardness of pure PbO. In addition, the strength of the composites was found to be 43 MPa, which is two times higher than that of pure PbO. The integrity of the composites was verified using the lead-bismuth eutectic alloy flushing experiment. The results of this research paper are important for future studies of oxygen control in the lead-bismuth eutectic alloy of lead-cooled fast reactors.

Nasal delivery of Fasudil-modified immune cells exhibits therapeutic potential in experimental autoimmune encephalomyelitis.

AIM: Multiple sclerosis (MS) is a relapsing-remitting inflammatory demyelinating disease that requires long-term treatment. Although Rho kinase inhibitor Fasudil shows good therapeutic effect in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, certain side effects may limit its clinical use. This study aimed at observing the therapeutic potential of Fasudil-modified encephalitogenic mononuclear cells (MNCs) via nasal delivery in EAE and exploring possible mechanisms of action. METHODS: Experimental autoimmune encephalomyelitis was induced with myelin oligodendrocyte glycoprotein 35-55 in C57BL/6 mice, and encephalitogenic MNCs were treated with Fasudil in vitro. Mice received 3 × 106  cells/10 µL per nasal cavity on day 3 and 11 postimmunization, respectively. RESULTS: Fasudil-modified MNCs reduced clinical severity of EAE, improved demyelination, and decreased inflammatory cells in spinal cords. Immunohistochemical results indicated that CD4+ T cells and CD68+ macrophages were barely detected in Fasudil-MNCs group. Fasudil-modified MNCs decreased CD4+ IFN-γ+ and CD4+ IL-17+ T cells, increased CD4+ IL-10+ T cells, restrained M1 markers CD16/32, CCR7, IL-12, CD8a, enhanced M2 markers CD206, CD200, CD14 in spleen. Fasudil-modified MNCs inhibited the activation of inflammatory signaling p-NF-kB/P38, accompanied by the decrease of COX-2 and the increase of Arg-1 in spinal cord, as well as the reduction of IL-17, TNF-α, IL-6 and the elevation of IL-10 in cultured supernatant of splenocytes. Fasudil-modified MNCs enhanced the levels of neurotrophic factors BDNF and NT-3 in spinal cord. CONCLUSION: Our results indicate that intranasal delivery of Fasudil-modified MNCs have therapeutic potential in EAE, providing a safe and effective cell therapeutic strategy to MS and/or other related disorders.

Aging and neurodegeneration are associated with increased mutations in single human neurons.

It has long been hypothesized that aging and neurodegeneration are associated with somatic mutation in neurons; however, methodological hurdles have prevented testing this hypothesis directly. We used single-cell whole-genome sequencing to perform genome-wide somatic single-nucleotide variant (sSNV) identification on DNA from 161 single neurons from the prefrontal cortex and hippocampus of 15 normal individuals (aged 4 months to 82 years), as well as 9 individuals affected by early-onset neurodegeneration due to genetic disorders of DNA repair (Cockayne syndrome and xeroderma pigmentosum). sSNVs increased approximately linearly with age in both areas (with a higher rate in hippocampus) and were more abundant in neurodegenerative disease. The accumulation of somatic mutations with age-which we term genosenium-shows age-related, region-related, and disease-related molecular signatures and may be important in other human age-associated conditions.

Melanocortin 4 Receptor Pathway Dysfunction in Obesity: Patient Stratification Aimed at MC4R Agonist Treatment.

Context: The hypothalamic melanocortin 4 receptor (MC4R) pathway serves a critical role in regulating body weight. Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), leptin receptor (LEPR), or MC4R genes, have been shown to cause early-onset severe obesity. Methods: Through a comprehensive epidemiological analysis of known and predicted LoF variants in the POMC, PCSK1, and LEPR genes, we sought to estimate the number of US individuals with biallelic MC4R pathway LoF variants. Results: We predict ~650 α-melanocyte-stimulating hormone (MSH)/POMC, 8500 PCSK1, and 3600 LEPR homozygous and compound heterozygous individuals in the United States, cumulatively enumerating >12,800 MC4R pathway-deficient obese patients. Few of these variants have been genetically diagnosed to date. These estimates increase when we include a small subset of less rare variants: ß-MSH/POMC,PCSK1 N221D, and a PCSK1 LoF variant (T640A). To further define the MC4R pathway and its potential impact on obesity, we tested associations between body mass index (BMI) and LoF mutation burden in the POMC, PCSK1, and LEPR genes in various populations. We show that the cumulative allele burden in individuals with two or more LoF alleles in one or more genes in the MC4R pathway are predisposed to a higher BMI than noncarriers or heterozygous LoF carriers with a defect in only one gene. Conclusions: Our analysis represents a genetically rationalized study of the hypothalamic MC4R pathway aimed at genetic patient stratification to determine which obese subpopulations should be studied to elucidate MC4R agonist (e.g., setmelanotide) treatment responsiveness.

Subthalamic nucleus lesions enhance the psychomotor-activating, incentive motivational, and neurobiological effects of cocaine.

The subthalamic nucleus (STN) is traditionally thought to be involved in motor control, and dysfunction of the STN is thought to contribute to movement disorders. Here, we show that the STN also plays an important role in motivational processes and the response to drugs of abuse. Specifically, bilateral STN lesions produced a dose-dependent increase in the psychomotor-activating effects of cocaine, the rate at which animals acquired cocaine self-administration, and the motivation for cocaine assessed using a progressive ratio schedule. Furthermore, bilateral STN lesions enhanced the ability of cocaine to induce gene expression in the nucleus accumbens and caudate-putamen, two structures known to be involved in mediating the psychomotor-activating and incentive motivational effects of drugs of abuse. These findings suggest that engagement of the STN serves to dampen the psychomotor-activating and incentive motivational effects of drugs of abuse. Thus, the STN may serve as a novel target for therapeutic interventions aimed at treating drug dependence.

Knockout of ERK1 enhances cocaine-evoked immediate early gene expression and behavioral plasticity.

The ability of cocaine to produce lasting neural adaptations in mesocorticolimbic brain regions is thought to promote drug seeking and facilitate addiction in humans. The Ras-controlled Raf-MEK-ERK protein kinase signaling cascade has been implicated in the behavioral and neurobiological actions of cocaine in animals. However, these pharmacological studies have not been able to determine the specific role of the two predominant isoforms of ERK (ERK1 and ERK2) in these processes. We report here that deletion of the ERK1 isoform, which leads to increased ERK2 stimulus-dependent signaling, facilitates the development of cocaine-induced psychomotor sensitization and the acquisition of a cocaine conditioned place preference. Conversely, pharmacological blockade of ERK signaling attenuates the development of psychomotor sensitization to cocaine. Finally, cocaine-evoked gene expression in mesocorticolimbic brain regions is potentiated in ERK1-deficient mice. Thus, alterations in ERK signaling influence both the neurobiological impact of cocaine and its ability to produce enduring forms of drug experience-dependent behavioral plasticity. Our results suggest that enhanced ERK2 signaling following repeated drug exposure may facilitate the development of forms of cocaine-induced plasticity that contribute to addiction.

Rapid delivery of nicotine promotes behavioral sensitization and alters its neurobiological impact.

BACKGROUND: Nicotine is highly addictive when it is inhaled from tobacco smoke, whereas nicotine replacement products, which usually deliver nicotine orally or transdermally, rarely lead to addiction. It has been proposed that this is due in part to differences in the rate of nicotine delivery to the brain under the two conditions. However, the mechanism by which rapid nicotine delivery facilitates the transition to addiction is not known. The ability of drugs to alter gene regulation and to produce sensitization has been implicated in addiction. We hypothesized, therefore, that varying the rate of nicotine administration may modulate its ability to elicit this form of plasticity. METHODS: Animals were treated with repeated intravenous infusions of nicotine over 5, 25, or 100 sec, and their locomotor responses were monitored over treatment days. RESULTS: We found that increasing the rate of intravenous nicotine infusion potentiated its ability to produce locomotor sensitization, and to induce c-fos and arc mRNA expression in mesocorticolimbic structures. CONCLUSIONS: We suggest that rapid administration may increase vulnerability to addiction by altering the neurobiological impact of nicotine and promoting a form of neurobehavioral plasticity (i.e., sensitization) that can lead to pathological incentive motivation for drugs.