Identification of Crucial Genes and Key Functions in Type 2 Diabetic Hearts by Bioinformatic Analysis.

Type 2 diabetes (T2D) patients with SARS-CoV-2 infection hospitalized develop an acute cardiovascular syndrome. It is urgent to elucidate underlying mechanisms associated with the acute cardiac injury in T2D hearts. We performed bioinformatic analysis on the expression profiles of public datasets to identify the pathogenic and prognostic genes in T2D hearts. Cardiac RNA-sequencing datasets from db/db or BKS mice (GSE161931) were updated to NCBI-Gene Expression Omnibus (NCBI-GEO), and used for the transcriptomics analyses with public datasets from NCBI-GEO of autopsy heart specimens with COVID-19 (5/6 with T2D, GSE150316), or dead healthy persons (GSE133054). Differentially expressed genes (DEGs) and overlapping homologous DEGs among the three datasets were identified using DESeq2. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses were conducted for event enrichment through clusterProfile. The protein-protein interaction (PPI) network of DEGs was established and visualized by Cytoscape. The transcriptions and functions of crucial genes were further validated in db/db hearts. In total, 542 up-regulated and 485 down-regulated DEGs in mice, and 811 up-regulated and 1399 down-regulated DEGs in human were identified, respectively. There were 74 overlapping homologous DEGs among all datasets. Mitochondria inner membrane and serine-type endopeptidase activity were further identified as the top-10 GO events for overlapping DEGs. Cardiac CAPNS1 (calpain small subunit 1) was the unique crucial gene shared by both enriched events. Its transcriptional level significantly increased in T2D mice, but surprisingly decreased in T2D patients with SARS-CoV-2 infection. PPI network was constructed with 30 interactions in overlapping DEGs, including CAPNS1. The substrates Junctophilin2 (Jp2), Tnni3, and Mybpc3 in cardiac calpain/CAPNS1 pathway showed less transcriptional change, although Capns1 increased in transcription in db/db mice. Instead, cytoplasmic JP2 significantly reduced and its hydrolyzed product JP2NT exhibited nuclear translocation in myocardium. This study suggests CAPNS1 is a crucial gene in T2D hearts. Its transcriptional upregulation leads to calpain/CAPNS1-associated JP2 hydrolysis and JP2NT nuclear translocation. Therefore, attenuated cardiac CAPNS1 transcription in T2D patients with SARS-CoV-2 infection highlights a novel target in adverse prognostics and comprehensive therapy. CAPNS1 can also be explored for the molecular signaling involving the onset, progression and prognostic in T2D patients with SARS-CoV-2 infection.

MicroRNA 181a-2-3p Alleviates the Apoptosis of Renal Tubular Epithelial Cells via Targeting GJB2 in Sepsis-Induced Acute Kidney Injury.

Acute kidney injury (AKI) is the most common complication of sepsis. MicroRNAs (miRNAs) play important roles in the sepsis-induced AKI. This paper aimed to explore the role of miRNA 181a-2-3p (miR-181a-2-3p) in the sepsis-induced AKI and the underlying mechanism. Our results revealed that miR-181a-2-3p showed low expression levels in patients with sepsis and mouse models undergoing cecal ligation and puncture (CLP). The addition of miR-181a-2-3p antagonists aggravated the sepsis-induced kidney injuries and inflammatory response in CLP mouse models, as suggested by hematoxylin and eosin (H&E) staining and quantitative real-time PCR (qRT-PCR). In addition, miR-181a-2-3p mimic alleviated the lipopolysaccharide (LPS)-induced inflammatory response, along with apoptosis of TCMK-1. Moreover, results from the GSE46955 data set indicated that GJB2 was highly expressed in septic patients but lowly expressed after recovery. Further, the dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were carried out, which confirmed that GJB2 was a target of miR-181a-2-3p, and overexpression of GJB2 reversed the anti-inflammatory and antiapoptotic effects of miR-181a-2-3p mimic on the LPS-induced sepsis cell models. In conclusion, miR-181a-2-3p alleviates the inflammatory response and cell apoptosis of septic patients and animal models by upregulating GJB2 expression, which may provide a new therapeutic strategy for sepsis.

Primary yolk sac tumor of pterygopalatine fossa with loss of vision: A case report.

INTRODUCTION: Primary yolk sac tumor (YST) is an infrequently-diagnosed malignant extragonadal germ cell tumors. It is likely to recur locally and may present with widespread metastases once diagnosed. Primary YST of the head is uncommon but can cause severe complications, such as loss of vision once the tumor mass invades the optic nerve. PATIENT CONCERNS: A 20-month-old boy presented to the general clinic of the local children's hospital with a complaint of swelling of left face for 1 year and proptosis of the left eye for over 2 weeks as stated by his parents. Initially, he did have some vision, as he could walk by himself, but a special ophthalmologic examination was not performed. DIAGNOSES: Cranial computed tomography and magnetic resonance imaging revealed a large tumor accompanied by peripheral bone destruction in the left pterygopalatine fossa that extended to sphenoid, ethmoid, left maxillary sinuses, left nasoethmoid, and left orbit. The optic nerve was invaded on both sides. Chest and abdominal imaging were normal. A primary diagnosis of Langerhans cell hyperplasia was made. However, blood tests on the second day of hospitalization revealed significantly elevated serum alpha-fetoprotein levels. On the third day, the boy lost his eyesight, with loss of pupillary and no light sensation during flashlight stimulation on both sides. INTERVENTIONS: Nasal endoscopy was performed on the fourth day, the vast majority of soft tissue mass was resected for biopsy. Histopathological examination revealed features of endodermal sinus tumor. A final diagnosis of primary YST of pterygopalatine fossa was made. Because the mass could not be resected completely, he received combined chemotherapy with bleomycin, etoposide, and carboplatin for 6 cycles over six months. OUTCOMES: The patient recovered with significant tumor shrinkage and without secondary metastasis after 18 months but left permanently blind. CONCLUSION: The worst complication of loss of vision after Primary YST of pterygopalatine fossa alerts us that close physical examination during the initial investigation should be performed, which is especially important in young children who cannot express complaints well. Early detection and treatment with surgical resection and chemotherapy may contribute to satisfactory outcomes and avoidance of visual impairment.

Gastric perforation following improper cardiopulmonary resuscitation in out-of-hospital cardiac arrest.

Gastric perforation is a rare complication of cardiopulmonary resuscitation (CPR), mostly resulting from incorrect airway management. If left unrecognized, it is associated with high mortality and morbidity. We present a case of gastric perforation after improper CPR. A 56-year-old drunken male was sent to the emergency department due to coma after fall onto the ground. He was thought to have cardiac arrest at scene and was saved with CPR maneuver by his friends who has never been trained before. He was taken to the hospital by emergency medical service personnel and presented with abdominal distention and extensive pneumoperitoneum. Emergency laparotomy was performed which revealed gastric perforation at the lesser curvature of the stomach. The laceration was repaired without any difficulty and the patient was discharged home without any neurological deficit. The aim of this report is to remind the public and emergency physicians that gastric perforation should be suspected in patients with distended abdomen and pneumoperitoneum after CPR. Because the most common risk factor for CPR-related gastric perforation is the bystander-provided resuscitation, it is encouraged for the public to take formal CPR training.

Atrial Natriuretic Peptide: A Potential Early Therapy for the Prevention of Multiple Organ Dysfunction Syndrome Following Severe Trauma.

Trauma remains a tremendous medical burden partly because of increased expenditure for the management of multiple organ dysfunction syndrome (MODS) developed during hospital stay. The intestinal barrier injury continues to be a second insult resulting in MODS which currently lacks efficient strategies for prevention. Recent studies have uncovered multi-organ protective benefits of atrial natriuretic peptide (ANP) in cardiovascular disease. However, the role of ANP in the prevention of MODS following severe trauma has not been understood. In our laboratory study, 1-h infusion of exogenous ANP during hemorrhagic shock following severe trauma induced high-level expression of endogenous serum ANP after 24 h, this effect was related to the improved level of functional biomarkers in multiple organs. Such phenomenon has not been found in other laboratories. A thorough literature review consequently was performed to uncover the potential mechanisms, to appraise therapy safety, and to propose uncertainties. In severe trauma, short-term exogenous ANP therapy during hemorrhagic shock may promote sustained endogenous expression of ANP from intestinal epithelium through activating a positive feedback loop mechanism involving phospholipase C-γ1 and reactive oxygen species crosstalk. This feedback loop may prevent MODS through multiple signaling pathways. Administration of ANP during hemorrhagic shock is thought to be safe. Further studies are required to confirm our proposed mechanisms and to investigate the dose, duration, and timing of ANP therapy in severe trauma.

Early goal-directed resuscitation for patients with severe sepsis and septic shock: a meta-analysis and trial sequential analysis.

BACKGROUND: The aim of this study was to explore whether early goal-directed therapy (EGDT) was associated with a lower mortality rate in comparison to usual care in patients with severe sepsis and septic shock. METHODS: PubMed, EMBASE, Cochrane library and a Chinese database (SinoMed) were searched systematically to identify randomized controlled trials (RCTs) comparing standard EGDT with usual care in resuscitation of patients with severe sepsis and septic shock and the search time could date back to the publication of the study by Rivers in 2001. The study selection, data extraction and methodological evaluation were performed by two investigators independently. The primary outcome was all-cause mortality. The present meta-analysis had been registered in PROSPERO (CRD42015017667). RESULTS: Our meta-analysis identified 6 studies and enrolling 4336 patients. There was no significant difference in mortality between the two groups, and the pooled odds ratio (OR) was 0.83 (95 % confident interval, CI, 0.64-1.08) with significant heterogeneity (p = 0.02, I(2) = 64%). However, the pooled OR of 3 multicenter RCTs was 1.03 (95% CI, 0.89-1.21) with no heterogeneity (p = 0.78, I(2) = 0%). The effects of EGDT on length of stay in the emergency department and intensive care unit were uncertain, and there was no effect of EGDT on hospital length of stay. There were no differences of mechanical ventilation rate and renal replacement therapy rate between the two groups, and patients in the EGDT group were more admitted in ICU than patients in the control group. During the early 6-h intervention period, patients in the EGDT group received more intravenous fluids, had a higher vasopressor usage rate, higher dobutamine usage rate and higher blood transfusion rate, than patients in the control group. Finally, there was no difference in the incidence of adverse events between the two groups, and the pooled OR was 1.06 (95%CI 0.80-1.39) with moderate heterogeneity (I(2) = 62%, p = 0.07). DISCUSSION: Our meta-analysis showed that the application of EGDT was not associated with lower mortality rate currently. However it does not mean that it is useless of EGDT in patients with sever sepsis and septic shock. On the contrary, there was no difference in mortality rate between the two groups may be due to the improvement of therapeutic strategies in these patients. And the results may be related to the different compliance rate of EGDT resuscitation bundle. CONCLUSIONS: The current evidence does not support the significant advantage of Early goal-directed therapy (EGDT) in the resuscitation of patients with severe sepsis and septic shock.

Ideal target arterial pressure after control of bleeding in a rabbit model of severe traumatic hemorrhagic shock: results from volume loading-based fluid resuscitation.

BACKGROUND: Previously reported ideal target mean arterial pressure (MAP) after control of bleeding in traumatic hemorrhagic shock (THS) requires further verification in more clinically related models. The authors explored this issue via gradient volume loading without vasopressor therapy. As certain volume loading can induce secretion of atrial natriuretic peptide (ANP), which has been shown to be protective, the authors also observed its potential role. MATERIALS AND METHODS: Fifty male New Zealand rabbits were submitted to 1.5 h of uncontrolled THS (with another eight rabbits assigned to the sham group). After bleeding control, treated rabbits were randomly (n = 10, respectively) resuscitated with blood and Ringer lactate (1:2) to achieve target MAP of 50, 60, 70, 80, and 90 mm Hg within 1 h. During the following 2 h, they were resuscitated toward baseline MAP. Rabbits were observed until 7 h. RESULTS: After resuscitation, infused fluid was lower and oxidative stress injury was milder in the 70 mm Hg group. Fluid volume loaded during the initial hour after hemostasis was negatively correlated with pH, oxygen saturation, and base excess at the end of resuscitation. It also correlated positively with proinflammatory responses in bronchoalveolar lavage fluid at 7 h and 7-h mortality. Moreover, after volume loading, the 80 mm Hg group showed significantly increased serum ANP level, which correlated with the expression of Akt protein in the jejunum at 7 h. CONCLUSIONS: In rabbits the ideal target MAP during the initial resuscitation of severe THS after hemostasis was 70 mm Hg. ANP may have a critical role in gut protection.

Determination of protein phosphatase type 2A in monocytes from multiple trauma patients: a potential biomarker for sepsis.

BACKGROUND: Protein phosphatase type 2A (PP2A) can downregulate c-Jun N-terminal kinase (JNK) expression in monocytes stimulated by lipopolysaccharide. However, this effect has not been evaluated in patients with sepsis. We sought to determine whether PP2A/JNK pathway is involved in sepsis and whether PP2A expression can be associated with patient outcome. MATERIALS AND METHODS: We measured PP2A, c-Jun, and JNK protein as well as PP2A and c-Jun messenger RNA in monocytes from trauma patients with (n = 24) or without (n = 22) sepsis 1 and 7 d after major trauma and from healthy volunteers (n = 15) by Western blotting and quantitative real-time polymerase chain reaction. Patient outcomes, including intensive care unit length of stay, Sequential Organ Failure Assessment score, and Multiple Organ Dysfunction score were compared between groups. Correlations between PP2A and c-Jun/JNK expression as well as patient outcomes were analyzed. Receiver operating characteristic analysis was performed to determine the diagnostic efficiency of PP2A for sepsis. RESULTS: PP2A protein and messenger RNA expression were significantly higher in septic patients compared with nonseptic patients or healthy volunteers. Conversely, the expressions of JNK and c-Jun were significantly reduced in septic patients and correlated inversely with PP2A expression. Furthermore, PP2A expression was positively associated with LOS, Sequential Organ Failure Assessment and Multiple Organ Dysfunction score at day 1 and day 7. Receiver operating characteristic curve yielded a high sensitivity (87.5%) of PP2A in discriminating septic versus nonseptic patients. CONCLUSIONS: PP2A may serve as a negative regulator of the JNK pathway and a biomarker for sepsis.

Evaluation of the inflammatory response in a two-hit acute lung injury model using [18F]FDG microPET.

The aim of this study was to investigate whether a two-hit acute lung injury (ALI) model is better than a one-hit model in simulating ALI, and to evaluate the inflammatory response in the lungs in these two models using micro-positron emission tomography (microPET) with [18F]fluorodeoxyglucose (FDG). Sprague Dawley rats were divided into four groups; rats in the lipopolysaccharide (LPS; n=10) and LPS-HCl (n=10) groups were challenged by the intraperitoneal administration of 5 mg/kg LPS, while rats in the normal saline (NS; n=3) and HCl (n=10) groups received the same volume of normal saline solution. Sixteen hours following the administration, the rats in the HCl and LPS-HCl groups received an acid instillation (IT) of 0.5 ml/kg HCl (pH=1.2), while the rats in the remaining two groups received the same volume of normal saline solution. The mean arterial blood pressure (MAP) and blood gas concentrations were measured in all four groups. MicroPET was performed 4 h following HCl IT and the lungs were excised for histopathological examination. The rats in the LPS-HCl group exhibited a higher arterial PaO2 and a lower arterial PaCO2 compared with the rats in the remaining groups. The MAP decreased markedly in the LPS-HCl group, but remained stable in the LPS, HCl and NS groups. MicroPET results identified that the region of interest ratio in the LPS-HCl group (9.00±1.41) was significantly higher compared with those in the LPS (4.01±0.60) and HCl (3.33±0.55) groups (P<0.01). In addition, histological examination showed that the mean lung injury score in the LPS-HCl group (12.70±0.95) was significantly higher compared with those in the HCl (8.40±1.26) and LPS (7.00±0.82) groups (P<0.01). The present study demonstrates that LPS pretreatment significantly magnifies and prolongs the inflammatory response to subsequent acid IT in the lungs. Moreover, it is simpler to induce ALI using the two-hit model than with the one-hit model, and [18F]FDG microPET is a useful tool for evaluating the inflammatory reaction during ALI.

Potential role of therapeutic hypothermia in the salvage of traumatic hemorrhagic shock.

Although therapeutic hypothermia could serve as a potential therapeutic strategy for treatment of traumatic hemorrhagic shock, significant controversy exists regarding its safety and feasibility. The current resuscitation strategy in traumatic hemorrhagic shock may also require updating. In this article, we have carried out an extensive literature search in this field and propose an initial algorithm for use of therapeutic hypothermia in traumatic hemorrhagic shock. This work lays essential groundwork for future investigations in this field.