Identification of potential biomarkers and therapeutic targets related to post-traumatic stress disorder due to traumatic brain injury.

BACKGROUND: Post-traumatic stress disorder (PTSD), a disease state that has an unclear pathogenesis, imposes a substantial burden on individuals and society. Traumatic brain injury (TBI) is one of the most significant triggers of PTSD. Identifying biomarkers associated with TBI-related PTSD will help researchers to uncover the underlying mechanism that drives disease development. Furthermore, it remains to be confirmed whether different types of traumas share a common mechanism of action. METHODS: For this study, we screened the eligible data sets from the Gene Expression Omnibus (GEO) database, obtained differentially expressed genes (DEGs) through analysis, conducted functional enrichment analysis on the DEGs in order to understand their molecular mechanisms, constructed a PPI network, used various algorithms to obtain hub genes, and finally evaluated, validated, and analyzed the diagnostic performance of the hub genes. RESULTS: A total of 430 upregulated and 992 down-regulated differentially expressed genes were extracted from the TBI data set. A total of 1919 upregulated and 851 down-regulated differentially expressed genes were extracted from the PTSD data set. Functional enrichment analysis revealed that the differentially expressed genes had biological functions linked to molecular regulation, cell signaling transduction, cell metabolic regulation, and immune response. After constructing a PPI network and introducing algorithm analysis, the upregulated hub genes were identified as VNN1, SERPINB2, and ETFDH, and the down-regulated hub genes were identified as FLT3LG, DYRK1A, DCN, and FKBP8. In addition, by comparing the data with patients with other types of trauma, it was revealed that PTSD showed different molecular processes that are under the influence of different trauma characteristics and responses. CONCLUSIONS: By exploring the role of different types of traumas during the pathogenesis of PTSD, its possible molecular mechanisms have been revealed, providing vital information for understanding the complex pathways associated with TBI-related PTSD. The data in this study has important implications for the design and development of new diagnostic and therapeutic methods needed to treat and manage PTSD.

Exploration of potential biomarkers and therapeutic targets for trauma-related acute kidney injury.

PURPOSE: Acute kidney injury (AKI) is one of the most common functional injuries observed in trauma patients. However, certain trauma medications may exacerbate renal injury. Therefore, the early detection of trauma-related AKI holds paramount importance in improving trauma prognosis. METHODS: Qualified datasets were selected from public databases, and common differentially expressed genes related to trauma-induced AKI and hub genes were identified through enrichment analysis and the establishment of protein-protein interaction (PPI) networks. Additionally, the specificity of these hub genes was investigated using the sepsis dataset and conducted a comprehensive literature review to assess their plausibility. The raw data from both datasets were downloaded using R software (version 4.2.1) and processed with the "affy" package19 for correction and normalization. RESULTS: Our analysis revealed 585 upregulated and 629 downregulated differentially expressed genes in the AKI dataset, along with 586 upregulated and 948 downregulated differentially expressed genes in the trauma dataset. Concurrently, the establishment of the PPI network and subsequent topological analysis highlighted key hub genes, including CD44, CD163, TIMP metallopeptidase inhibitor 1, cytochrome b-245 beta chain, versican, membrane spanning 4-domains A4A, mitogen-activated protein kinase 14, and early growth response 1. Notably, their receiver operating characteristic curves displayed areas exceeding 75%, indicating good diagnostic performance. Moreover, our findings postulated a unique molecular mechanism underlying trauma-related AKI. CONCLUSION: This study presents an alternative strategy for the early diagnosis and treatment of trauma-related AKI, based on the identification of potential biomarkers and therapeutic targets. Additionally, this study provides theoretical references for elucidating the mechanisms of trauma-related AKI.

A novel artificial intelligence-assisted triage tool to aid in the diagnosis of suspected COVID-19 pneumonia cases in fever clinics.

BACKGROUND: Currently, the need to prevent and control the spread of the 2019 novel coronavirus disease (COVID-19) outside of Hubei province in China and internationally has become increasingly critical. We developed and validated a diagnostic model that does not rely on computed tomography (CT) images to aid in the early identification of suspected COVID-19 pneumonia (S-COVID-19-P) patients admitted to adult fever clinics and made the validated model available via an online triage calculator. METHODS: Patients admitted from January 14 to February 26, 2020 with an epidemiological history of exposure to COVID-19 were included in the study [model development group (n=132) and validation group (n=32)]. Candidate features included clinical symptoms, routine laboratory tests, and other clinical information on admission. The features selection and model development were based on the least absolute shrinkage and selection operator (LASSO) regression. The primary outcome was the development and validation of a diagnostic aid model for the early identification of S-COVID-19-P on admission. RESULTS: The development cohort contained 26 cases of S-COVID-19-P and seven cases of confirmed COVID-19 pneumonia (C-COVID-19-P). The final selected features included one demographic variable, four vital signs, five routine blood values, seven clinical signs and symptoms, and one infection-related biomarker. The model's performance in the testing set and the validation group resulted in area under the receiver operating characteristic (ROC) curves (AUCs) of 0.841 and 0.938, F1 scores of 0.571 and 0.667, recall of 1.000 and 1.000, specificity of 0.727 and 0.778, and precision of 0.400 and 0.500, respectively. The top five most important features were age, interleukin-6 (IL-6), systolic blood pressure (SYS_BP), monocyte ratio (MONO%), and fever classification (FC). Based on this model, an optimized strategy for the early identification of S-COVID-19-P in fever clinics has also been designed. CONCLUSIONS: A machine-learning model based solely on clinical information and not on CT images was able to perform the early identification of S-COVID-19-P on admission in fever clinics with a 100% recall score. This high-performing and validated model has been deployed as an online triage tool, which is available at https://intensivecare.shinyapps.io/COVID19/.

Prediction of fatal adverse prognosis in patients with fever-related diseases based on machine learning: A retrospective study.

BACKGROUND: Fever is the most common chief complaint of emergency patients. Early identification of patients at an increasing risk of death may avert adverse outcomes. The aim of this study was to establish an early prediction model of fatal adverse prognosis of fever patients by extracting key indicators using big data technology. METHODS: A retrospective study of patients' data was conducted using the Emergency Rescue Database of Chinese People's Liberation Army General Hospital. Patients were divided into the fatal adverse prognosis group and the good prognosis group. The commonly used clinical indicators were compared. Recursive feature elimination (RFE) method was used to determine the optimal number of the included variables. In the training model, logistic regression, random forest, adaboost and bagging were selected. We also collected the emergency room data from December 2018 to December 2019 with the same inclusion and exclusion criterion. The performance of the model was evaluated by accuracy, F1-score, precision, sensitivity and the areas under receiver operator characteristic curves (ROC-AUC). RESULTS: The accuracy of logistic regression, decision tree, adaboost and bagging was 0.951, 0.928, 0.924, and 0.924, F1-scores were 0.938, 0.933, 0.930, and 0.930, the precision was 0.943, 0.938, 0.937, and 0.937, ROC-AUC were 0.808, 0.738, 0.736, and 0.885, respectively. ROC-AUC of ten-fold cross-validation in logistic and bagging models were 0.80 and 0.87, respectively. The top six coefficients and odds ratio (OR) values of the variables in the Logistic regression were cardiac troponin T (CTnT) (coefficient=0.346, OR = 1.413), temperature (T) (coefficient=0.235, OR = 1.265), respiratory rate (RR) (coefficient= -0.206,OR = 0.814), serum kalium (K) (coefficient=0.137, OR = 1.146), pulse oxygen saturation (SPO2) (coefficient= -0.101, OR = 0.904), and albumin (ALB) (coefficient= -0.043, OR = 0.958). The weights of the top six variables in the bagging model were: CTnT, RR, lactate dehydrogenase, serum amylase, heartrate, and systolic blood pressure. CONCLUSIONS: The main clinical indicators of concern included CTnT, RR, SPO2, T, ALB and K. The bagging model and logistic regression model had better diagnostic performance comprehesively. Those may be conducive to the early identification of critical patients with fever by physicians.

Therapeutic effect of ultrasound interventional perirenal catheter-assisted early peripancreatic lavage of protease inhibitor on severe acute pancreatitis in miniature pigs.

OBJECTIVES: To study the therapeutic effect of early peripancreatic lavage of ulinastatin on severe acute pancreatitis(SAP). METHODS: Sixteen pigs were divided into 4 groups: model(SAP), saline lavage(SL), ulinastatin lavage(UL), intravenous ulinastatin(IU). UL and SL group were given peripancreatic lavage of ulinastatin by ultrasound-guided perirenal catheterization and IU group was intravenously instilled with ulinastatin. The multi-organ functions and the inflammatory factors were observed. RESULTS: UL group has the best therapeutic effect. The changes of multi-organ functions and the inflammatory factors were compared with SAP group as follows. In time window of treatment: amylase (p < 0.01), lipase (p < 0.01), ALT (p > 0.05), AST (p < 0.05), CR (p < 0.01), UR (p < 0.01), IL-6 (p < 0.01), IL-10 (p < 0.01). In post-treatment phase: amylase (p < 0.01), lipase (p < 0.01), ALT (p < 0.01), AST (p < 0.01), CR (p < 0.05), UR (p > 0.05), IL-6 (p < 0.01), IL-10 (p < 0.01). CONCLUSIONS: Early peripancreatic lavage of ulinastatin in SAP could effectively improve the multi-organ functions and inflammatory response.

Association between the T6459C point mutation of the mitochondrial MT-CO1 gene and susceptibility to sepsis among Chinese Han people.

To search for an association between sepsis and mitochondrial genetic basis, we began our study. In this study, a proband harbouring mitochondrial T6459C mutation with sepsis and his Chinese Han pedigree including 7 members of 3 generations were enrolled. General information, blood parameters and mitochondrial full sequence scanning of all members were performed, and cellular functions, including cellular reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), degrees of cell apoptosis and adenosine triphosphate (ATP) concentrations, were measured in members with and without the T6459C mutation. Through mitochondrial full sequence scanning and analysis of all members we found, the maternal members (I-1, II-1, II-2 and II-4) in this Chinese Han pedigree all had the mitochondrial T6459C mutation and were used as the mutation group. The non-maternal members (II-3, III-1 and III-2) did not have this mutation and were used as the non-mutation group. The differences in all indicators, including the blood routine, blood biochemistry and coagulation function tests, between members in these two groups were not significant. Under the non-stimulation condition, the mutation group had higher ROS levels (4210.42 ± 1043.35 vs 3387.78 ± 489.66, P = .028) and apoptosis ratios (P = .004) and lower ATP concentrations (P = .049) and MMP levels (P = .047) than the non-mutation group. After 6 hours of simulated LPS stimulation, the mutation group had significantly increased ROS levels (5759.25 ± 2297.90 vs 3862.00 ± 1519.77, P = .045) compared with the non-mutation group, whereas the mutation group continued to demonstrate higher ROS levels (P = .045) and apoptosis ratios (P = .003) and lower MMP levels (P = .005) and ATP concentrations (P = .010). We speculated that the mtDNA T6459C mutation might be the basis for the genetic susceptibility to sepsis.

Identification of potential key genes associated with severe pneumonia using mRNA-seq.

This study aimed to identify the potential key genes associated with severe pneumonia using mRNA-seq. Nine peripheral blood samples from patients with severe pneumonia alone (SP group, n=3) and severe pneumonia accompanied with chronic obstructive pulmonary disease (COPD; CSP group, n=3), as well as volunteers without pneumonia (control group, n=3) underwent mRNA-seq. Based on the sequencing data, differentially expressed genes (DEGs) were identified by Limma package. Following the pathway enrichment analysis of DEGs, the genes that were differentially expressed in the SP and CSP groups were selected for pathway enrichment analysis and coexpression analysis. In addition, potential genes related to pneumonia were identified based on the information in the Comparative Toxicogenomics Database. In total, 645 and 528 DEGs were identified in the SP and CSP groups, respectively, compared with the normal controls. Among these DEGs, 88 upregulated genes and 80 downregulated genes were common between the two groups. The functions of the common DEGs were similar to those of the DEGs in the SP group. In the coexpression network, the commonly downregulated genes (including ND1, ND3, ND4L, and ND6) and the commonly upregulated genes (including TSPY6P and CDY10P) exhibited a higher degree. In addition, 131 DEGs (including ND1, ND3, ND6, MIR449A and TAS2R43) were predicted to be potential pneumonia-related genes. In conclusion, the present study demonstrated that the common DEGs may be associated with the progression of severe pneumonia.

Deep cerebral microbleeds are associated with the severity of lacunar infarcts and hypertension: A retrospective analysis.

Cerebral microbleeds (CMBs) and lacunar infarcts are common manifestations of cerebral small vessel disease. However, the association between the location of CMBs and lacunar infarcts is unclear. Our study aimed to clarify the relationship between the location of CMBs and lacunar infarcts.This study retrospectively analyzed 166 patients with ischemic stroke or transient ischemic attacks admitted in the Geriatric Neurology Department of Chinese PLA General Hospital between February 2010 and December 2012. We collected clinical characteristics and risk factors of CMBs. The location of CMBs on T2*-weighted angiography was assessed by the Microbleed Anatomical Rating Scale. The number of lacunar infarcts and the severity of white matter hyperintensities were also recorded. The association between the location of CMBs and lacunar infarcts parameters was examined.CMBs were present in 77 (46.4%) patients. The presence [odds ratios (OR), 2.14; 95% confidence interval (CI), 1.02-4.48], number (OR, 1.17; 95% CI, 1.02-1.36 per lesion), severity (OR, 1.61; 95% CI, 1.07-2.42) of lacunar infarcts, and hypertension (OR, 5.76; 95% CI, 2.01-16.55) were independent risk factors for CMBs. Stratified by the location of CMBs, lobar CMBs and infratentorial CMBs did not show significant association with lacunar infarcts. Deep CMBs were significantly associated with the number (OR 1.18, 95% CI 1.03-1.36) and severity (OR 1.71, 95% CI 1.11-2.63) of lacunar infarcts. Moreover, the percentage of deep CMBs increased with the increased severity of lacunar infarcts (P = .003).Deep CMBs rather than lobar and infratentorial CMBs are associated with lacunar infarcts.

Clinical analysis of 215 consecutive cases with fever of unknown origin: A cohort study.

Fever of unknown origin (FUO) is a frequently observed phenomenon in clinical practice. The present study was aimed to investigate potential causes of FUO, thereby improving clinical diagnosis of this disorder.In this retrospective study, clinical data were collected from 215 patients who were diagnosed with FUO between January 2009 and December 2010, and an 18 to 36 months follow-up visit was also performed for these patients.Among these FUO cases, the most common causes of the disease were infectious diseases (IDs) (42.3%), followed by connective tissue diseases (CTDs) (32.1%), miscellaneous (Mi) (10.7%) and neoplasm (N) (6.5%), while the causes for the other 18 cases (8.4%) were still unknown. The most common types of ID, CTD, and N were tuberculosis (16/91, 17.6%), adult onset Still disease (AOSD) (37/69, 53.6%) and non-Hodgkin lymphoma (6/14, 42.9%), respectively.IDs still represent the most common causes of FUO. Regularly intermittent fever with urinary infections and irregularly intermittent fever with infective endocarditis may be regarded as some signs in clinical diagnosis of FUO.

Identification of miRNA biomarkers of pneumonia using RNA-sequencing and bioinformatics analysis.

Pneumonia is a lower respiratory tract infection that causes dramatic mortality worldwide. The present study aimed to investigate the pathogenesis of pneumonia and identify microRNA (miRNA) biomarkers as candidates for targeted therapy. RNA from the peripheral blood plasma of participants with pneumonia (severe, n=9; non-severe, n=9) and controls (n=9) was isolated and paired-end sequencing was performed on an Illumina HiSeq4000 system. Following the processing of raw reads, the sequences were aligned against the Genome Reference Consortium human genome assembly 38 reference genome using Bowtie2 software. Reads per kilobase of transcript per million mapped read values were obtained and the limma software package was used to identify differentially expressed miRNAs (DE-miRs). Then, DE-miR targets were predicted and subjected to enrichment analysis. In addition, a protein-protein interaction (PPI) network of the predicted targets was constructed. This analysis identified 11 key DE-miRs in pneumonia samples, including 6 upregulated miRNAs (including hsa-miR-34a and hsa-miR-455) and 5 downregulated miRNAs (including hsa-let-7f-1). All DE-miRs kept their upregulation/downregulation pattern in the control, non-severe pneumonia and severe pneumonia samples. Predicted target genes of DE-miRs in the subjects with non-severe pneumonia vs. the control and the subjects with severe pneumonia vs. the non-severe pneumonia group were markedly enriched in the adherens junction and Wnt signaling pathways. KALRN, Ras homolog family member A (RHOA), ß-catenin (CTNNB1), RNA polymerase II subunit K (POLR2K) and amyloid precursor protein (APP) were determined to encode crucial proteins in the PPI network constructed. KALRN was predicted to be a target of hsa-mir-200b, while RHOA, CTNNB1, POLR2K and APP were predicted targets of hsa-let-7f-1. The results of the present study demonstrated that hsa-let-7f-1 may serve a role in the development of cancer and the Notch signaling pathway. Conversely, hsa-miR-455 may be an inhibitor of pneumonia pathogenesis. Furthermore, hsa-miR-200b might promote pneumonia via targeting KALRN.

Anti­aging effects of melatonin on the myocardial mitochondria of rats and associated mechanisms.

The present study investigated the anti-aging effects of melatonin on the myocardial mitochondria of D-galactose-aged rats and associated mechanisms. A total of 30 male Sprague­Dawley (SD) rats were randomly divided into three equal groups: An accelerated aging group that received 125 mg/kg/day D­galactose; a melatonin­treated group of D­galactose­aged rats that received 10 mg/kg/day melatonin; and a control group receiving normal saline. ATP, ADP and AMP levels in the left ventricular myocardium of rats were determined by high performance liquid chromatography and the total adenylic acid number (TAN) was subsequently calculated. Bax, Bcl­2, and cytochrome c (cyt­c) protein expression levels in myocardial mitochondria and cytoplasm were quantified by western blot analysis. In the melatonin­treated group, ATP levels were significantly higher when compared with the untreated control group and the accelerated­ageing group (0.068 vs. 0.052 and 0.058; P=0.002 and P=0.045, respectively), and TAN was significantly increased in the melatonin­treated group when compared with controls (P=0.011). In addition, cyt­c levels in the cytoplasm, but not in the mitochondria, were significantly higher in the accelerated­aging group compared with the control and melatonin­treated groups (P=0.001 and P=0.002, respectively). Bcl­2 and Bax ratios were significantly higher in the control and melatonin­treated groups when compared with the accelerated­aging group (P=0.004 and P=0.032, respectively). These results suggest that melatonin exhibits a protective effect on mitochondrial function in a rat model of accelerated aging.

A New Insight Into Sudden Cardiac Death in Young People: A Systematic Review of Cases of Takotsubo Cardiomyopathy.

Takotsubo cardiomyopathy (TTC) causes sudden cardiac death and has garnered increased attention worldwide in recent years. However, few studies have clearly classified the risk factors for this disease, including gender, race and morbidity, as well as the physical and mental stressors that can exacerbate the disease, particularly in young patients. To better analyze the characteristics of young TTC patients, we performed a systematic review of reported cases involving young patients.A computer-assisted search was performed using prominent electronic medical information sources to identify literature published between January 1965 and December 2013. Relevant studies containing clinical data of young TTC patients were included.Ninety-six records that included information about 104 cases were ultimately selected for our review. Several of the following results were noted: First, physical stress was more likely to exacerbate TTC than was mental stress in young patients. Second, more female than male TTC patients were noted among both young patients and the general population. Third, ethnicity appears to play no role in the disease, as no significant differences were noted among individuals of different races with respect to clinical characteristics, morbidity or stressors. Fourth, the clinical manifestations of TTC were similar to those of other cardiac diseases, including coronary heart disease. However, TTC may be detected using the combination of echocardiography and ventriculography.Clinicians should consider TTC if young patients present with symptoms similar to those of coronary heart disease so that harmful treatments such as coronary artery stent placement may be avoided. Moreover, the answers to questions regarding the clinical diagnostic criteria, etiology, pathophysiology, and the management of this syndrome in youth remain unclear; therefore, further research is needed.

[Muscle tissue lymphoma presenting only with fever of unknown origin: a case report and literature review].

OBJECTIVE: Extra-nodal malignant lymphoma is often characterized by a lack of typical symptoms and positive results of auxiliary examinations, which make diagnosis difficult. In some cases, fever can be the only clinical manifestation. For the lymphoma patients presenting with persistent fever with a duration over 3 weeks, characteristics of fever including time of fever attack, fever type and effects of drugs may have significant value in the diagnosis, especially in the early stage of the disease or in rare cases.

Effects of emotional and physiological stress on plaque instability in apolipoprotein E knockout mice

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In the present study, we sought to investigate the effects of emotional and physiological stress on plaque instability in atherosclerosis. We used different stress-treated apolipoprotein E (ApoE)-deficient mice, which have been shown to spontaneously develop atherosclerosis with features similar to those seen in humans, as an animal model. Morphology study showed that emotional stress (ES) obviously promoted the development of atherosclerotic plaques and plaque instability evidenced by significantly increasing plaque size, plaque-to-surface ratio and plaque calcification, and enhancing the frequency of large necrotic core and medial erosion compared with control (..) (AU)

Effects of emotional and physiological stress on plaque instability in apolipoprotein E knockout mice.

In the present study, we sought to investigate the effects of emotional and physiological stress on plaque instability in atherosclerosis. We used different stress-treated apolipoprotein E (ApoE)-deficient mice, which have been shown to spontaneously develop atherosclerosis with features similar to those seen in humans, as an animal model. Morphology study showed that emotional stress (ES) obviously promoted the development of atherosclerotic plaques and plaque instability evidenced by significantly increasing plaque size, plaque-to-surface ratio and plaque calcification, and enhancing the frequency of large necrotic core and medial erosion compared with control ApoE(-/-) mice (P<0.01). Physiological stress (PS) treatment alone did not affect the plaque stability compared with control ApoE(-/-) mice (P>0.05). However, the combination of ES and PS treatment (CS) initiated much stronger plaque instability compared with ES treatment alone (P<0.01), increased the frequency of thin fibrous caps, and even triggered plaque rupture and buried fibrous cap. Immunohistochemical analysis indicated that both ES and CS treatment led to an increase in the accumulation of macrophages and T cells and a decrease of smooth muscle cells, reflecting an unstable atherosclerotic plaque phenotype, in the atherosclerotic lesions in ApoE(-/-) mice. PS alone did not affect plaque cellular components. Similarly, CS-mediated changes in atherosclerotic plaque composition were stronger than that caused by ES alone (P<0.01). Taken together, ES treatment alone is sufficient to promote plaque instability. PS alone does not affect atherosclerotic plaque development, but can potentiate ES-mediated plaque destabilization.

Chronic unpredictable stress accelerates atherosclerosis through promoting inflammation in apolipoprotein E knockout mice.

INTRODUCTION: Chronic unpredictable stress (CUS) has been suggested to accelerate atherosclerosis. However, the underlying mechanism of this adverse effect is not fully understood. Since chronic stress can promote or even initiate inflammation response, which is thought to be a major contributor to atherogenesis, we postulated that stress-induced inflammatory response might be one important reason for CUS-promoted atherosclerotic disease. MATERIALS AND METHODS: We used the CUS treated apolipoprotein E (ApoE)-deficient mice, which have been shown to spontaneously develop atherosclerosis with features similar to those seen in humans, as an animal model. Haematoxylin and eosin staining and immunohistostaining were used to analyze the plaque formation and composition. RESULTS: Histological analysis clearly demonstrated that CUS treatment promoted the development of atherosclerotic lesions, such as triggering plaque rupture, increasing plaque size and plaque-to-surface ratio, and also led to profound changes in plaque composition, as evidenced by increased macrophage and T cell infiltration and decreased smooth muscle cell mass, all reflecting an unstable plaque phenotype. Moreover, adhesion molecular vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), acute phase reactant C-reactive protein (CRP), and proinflammatory cytokine interleukin-6 (IL-6) were significantly enhanced in CUS treated ApoE(-/-) mice compared with untreated control animals (P<0.01). CONCLUSION: The involvement of CUS in the pathogenesis of atherosclerosis is at least partially attributable to its acceleration of inflammation.