Could extracellular vesicles derived from mesenchymal stem cells be a potential therapy for acute pancreatitis-induced cardiac injury?

Acute pancreatitis (AP) often leads to a high incidence of cardiac injury, posing significant challenges in the treatment of severe AP and contributing to increased mortality rates. Mesenchymal stem cells (MSCs) release bioactive molecules that participate in various inflammatory diseases. Similarly, extracellular vesicles (EVs) secreted by MSCs have garnered extensive attention due to their comparable anti-inflammatory effects to MSCs and their potential to avoid risks associated with cell transplantation. Recently, the therapeutic potential of MSCs-EVs in various inflammatory diseases, including sepsis and AP, has gained increasing recognition. Although preclinical research on the utilization of MSCs-EVs in AP-induced cardiac injury is limited, several studies have demonstrated the positive effects of MSCs-EVs in regulating inflammation and immunity in sepsis-induced cardiac injury and cardiovascular diseases. Furthermore, clinical studies have been conducted on the therapeutic application of MSCs-EVs for some other diseases, wherein the contents of these EVs could be deliberately modified through prior modulation of MSCs. Consequently, we hypothesize that MSCs-EVs hold promise as a potential therapy for AP-induced cardiac injury. This paper aims to discuss this topic. However, additional research is essential to comprehensively elucidate the underlying mechanisms of MSCs-EVs in treating AP-induced cardiac injury, as well as to ascertain their safety and efficacy.

SOFA score is superior to APACHE-II score in predicting the prognosis of critically ill patients with acute kidney injury undergoing continuous renal replacement therapy.

BACKGROUND: Acute kidney injury (AKI) is the most common cause of organ failure in multiple organ dysfunction syndrome (MODS) and is associated with increased mortality. This study aimed at determining the efficacy of sequential organ failure assessment (SOFA), and acute physiology and chronic health evaluation II (APACHE-II) scoring systems in assessing the prognosis of critically ill patients with AKI undergoing CRRT. METHODS: The predictive value of SOFA and APACHE-II scores for 28- and 90-d mortality in patients with AKI undergoing continuous renal replacement therapy (CRRT) were determined by multivariate analysis, sensitivity analysis, and curve-fitting analysis. RESULTS: A total of 836 cases were included in this study. Multivariate Cox logistic regression analysis showed that SOFA scores were associated with 28- and 90-d mortality in patients with AKI undergoing CRRT. The adjusted HR of SOFA for28-d mortality were 1.18 (1.14, 1.21), 1.24 (1.18, 1.31), and 1.19 (1.13, 1.24) in the three models, respectively, and the adjusted HR of SOFA for 90-d mortality was 1.12 (1.09, 1.16), 1.15 (1.10, 1.19), and 1.15 (1.10, 1.19), respectively. The subgroup analysis showed that the SOFA score was associated with 28-d and 90-d mortality in patients with AKI undergoing CRRT. APACHE-II score was not associated with 28- and 90-d mortality patients with AKI undergoing CRRT. Curve fitting analysis showed that SOFA scores increased had a higher prediction accuracy for 28- and 90-d than APACHE-II. CONCLUSIONS: The SOFA score showed a higher accuracy of mortality prediction in critically ill patients with AKI undergoing CRRT than the APACHE-II score.

A Retrospective Population Study to Develop a Predictive Model of Prediabetes and Incident Type 2 Diabetes Mellitus from a Hospital Database in Japan Between 2004 and 2015.

BACKGROUND Type 2 diabetes mellitus is a global public health problem. Prediabetes may be reversed by weight loss, diet, and lifestyle changes. However, without intervention, between 30-50% of individuals with prediabetes develop type 2 diabetes. This retrospective population study was conducted to develop a predictive model of prediabetes and incident type 2 diabetes mellitus using data from 2004 to 2015 from the DRYAD Japanese hospital database. MATERIAL AND METHODS A retrospective longitudinal population study was conducted using the DRYAD database from Murakami Memorial Hospital, Gifu, Japan, to construct a predictive model for prediabetes and incident type 2 diabetes mellitus in the population. Univariate analysis and multivariate analysis were performed to identify the variables that were associated with prediabetes. These variables were used to construct (75% samples) and verify (25% samples) the predictive model. RESULTS From 2004 to 2015, a total of 11,113 cases were identified. Multivariate logistic regression analysis included the six variables of age, waist circumference, smoking history, the presence of fatty liver, fasting blood glucose (FBG), and glycated hemoglobin (HbA1c) level. Data were used to construct (75% samples) and verify (25% samples) in a predictive model. The area under the receiver operating characteristic (ROC) curve (AUC) of the predictive model was 0.87 (0.85-0.89) in the training cohort and 0.87 (0.86-0.90) in the validation cohort. CONCLUSIONS A prognostic model based on six variables was predictive for incident type 2 diabetes mellitus and prediabetes in a healthy population in Japan.

Treating aplasia cutis congenita in a newborn with the combination of ionic silver dressing and moist exposed burn ointment: A case report.

BACKGROUND: Aplasia cutis congenita (ACC) in newborns is a condition in which congenital defects or hypoplasia is present in part of the epidermis, dermis and even subcutaneous tissue (including muscle and bones). First reported by Cordon in 1767, ACC is a rare disease with a low incidence of 1/100000 to 3/10000. Currently, there are 500 cases reported worldwide. ACC can be accompanied by other malformations. The onset mechanism of the disease remains unknown but is thought to be correlated to factors such as genetics, narrow uterus, foetal skin and amniotic membrane adhesion, use of teratogenic drugs in early pregnancy and viral infection. CASE SUMMARY: In August 2018, we treated a newborn with ACC on the left lower limbs using a combination of ionic silver dressing and moist exposed burn ointment (MEBO) and achieved a satisfactory treatment outcome. The skin defects were observed on the external genitals and on areas from the left foot to 3/4 of the upper left side. Subcutaneous tissue and blood vessels were observed in the regions with skin defects. The following treatments were provided. First, the wound was rinsed with 0.9% sodium chloride solution followed by disinfection with povidone-iodine twice. And then MEBO was applied to the wound at a thickness of approximately 1 mm. After applying ionic silver dressing, the wound was covered with sterile gauze. The wound dressing was replaced every 2-3 d. At the 4-mo follow-up, the treatment outcome was satisfactory. There was minimal scar tissue formation, and limb function was not impaired. CONCLUSION: The combination of ionic silver dressing and MEBO to ACC is helpful.

Higher body mass index is not a protective risk factor for 28-days mortality in critically ill patients with acute kidney injury undergoing continuous renal replacement therapy.

Background: Acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) is a fatal and common clinical disorder in critically ill patients. Recent studies have shown that the relationship between BMI and the outcome of patients with AKI undergoing CRRT is conflicting. Methods: A retrospective cohort study based on data reuse. Univariate analysis, multi-factor regression analysis and subgroup analyses were used to explore the association of the BMI with the 28-days mortality risk in patients with AKI undergoing CRRT. Results: From January 2009 to September 2016, a total of 1120 cases met the inclusion criteria and were enrolled in this study. The univariate analysis showed that BMI was associated with 28-days mortality of patients with AKI undergoing CRRT, its HR value was 0.98 (0.96, 0.99). The multi-factor regression analysis showed that BMI was not associated with 28-days mortality of patients with AKI undergoing CRRT in the four models, the adjusted HR value of four models were 1.00 (0.96, 1.04), 1.01 (0.97, 1.04), 1.00 (0.96, 1.04) and 1.00 (0.96, 1.04), respectively. The subgroups analyses showed that the BMI was a risk factor of the 28-days mortality in patients with AKI undergoing CRRT when GFR ≥30 mL/min, its HR value was 1.04 (1.01, 1.09). Conclusion: Higher BMI was not a protective risk of 28-day mortality in patients with AKI undergoing CRRT. Especially, when GFR ≥30 mL/min, higher BMI increased the risk of the 28-day mortality rate in patients with AKI undergoing CRRT.

The related factors for the recovery and maintenance time of sinus rhythm in hospitalized patients with cardiopulmonary resuscitation: A single-center retrospective case-control study.

No matter in or outside hospital, the success rate of cardiopulmonary resuscitation (CPR) is very low. The sign of successful CPR is the recovery of spontaneous circulation. The premise of the recovery of spontaneous circulation is the recovery and maintenance of sinus rhythm, but there is still no related research.We aim to study the factors for the recovery and maintenance time of sinus rhythm in patients with CPR.A single-center retrospective case-control study.Ethical review was obtained (ethical approval number: 20180031).The second affiliated hospital of Xi'an Jiaotong University, Xi'an Shaanxi, China.From January 2011 to December 2016, totally 344 cases met the inclusion and exclusion criteria, sinus rhythm recovered group (SR group) (n = 130 cases), sinus rhythm unrecovered group (SUR group) (n = 214 cases).The multivariate logistic regression analysis showed that red blood cell counts (OR = 1.30, 95% CI:1.04-1.63, P = .02), rescue time (OR = 0.95, 95% CI:0.94-0.97, P <.001), the usage of norepinephrine (OR = 2.14, 95% CI:1.06-4.35, P = .04) were important factor for the recovery of sinus rhythm in patients with CPR. Multivariate linear regression analysis showed that the dosage of epinephrine, the usage of naloxone and diagnosis were important factors for maintenance time of sinus rhythm after resuscitation, P <.05. The rescue time had high accuracy to predict the recovery of sinus rhythm, the area under the receiver operator characteristic (ROC) curve (AUC) was 0.84 (0.80, 0.88), sensitivity and specificity are respectively 71.54% and 93.46%.Red blood cell counts, the rescue time and the usage of norepinephrine might be important factors for the recovery of sinus rhythm, and the dosage of epinephrine, the usage of naloxone and the diagnosis might be important factors for the maintenance time of sinus rhythm in patients with CPR.

Augmenter of liver regeneration (ALR) regulates acute pancreatitis via inhibiting HMGB1/TLR4/NF-κB signaling pathway.

This research aimed to explore the effect of augmenter of liver regeneration (ALR) in acute pancreatitis (AP) of mice and the underlying mechanism. Caerulein were given to mice to get AP models. AP mice were given saline, ALR plasmids or negative control plasmids. Then, pancreas tissues were fixed and stained for histological examination. The levels of serum amylase, serum lipase, MPO, HMGB1, TNF-α, IL-1ß as well as MCP-1 were detected by ELISA assay. The mRNA levels of TLR4, p65, IκBα, iNOS, COX-2 and GAPDH were examined by RT-qPCR. The protein levels of HMGB1, TLR4, MD2, MyD88, IκBα and GAPDH were detected by western blotting. ALR decreased serum amylase as well as lipase levels and alleviated the histopathological alterations of the pancreas in AP mice. ALR decreased the MPO activity of pancreas in AP Mice. ALR decreased the HMGB1/TLR4 signaling pathway in AP Mice. ALR decreased pancreas IL-1ß and MCP-1 in AP mice, and also decreased plasma TNF-α and IL-1ß in AP mice. ALR attenuated the cerulein-caused increase in p65 mRNA and protein levels, but had no effects on mRNA and protein levels of IκBα. The AP mice significantly promoted the mRNA levels of iNOS and COX-2 that was inhibited by ALR. HNE formation was also increased in AP mice, but it was decreased by ALR. ALR alleviates acute pancreatitis by inhibiting HMGB1/TLR4/NF-κB signaling pathway. It is promising to alleviate the syndromes of patients with acute via targeting ALR.

Downregulation of Akt2 attenuates ER stress-induced cytotoxicity through JNK-Wnt pathway in cardiomyocytes.

Akt, also known as protein kinase B (PKB), is a serine/threonine kinase that promotes survival and growth in response to extracellular signals. Akt1 has been demonstrated to play vital roles in cardiovascular diseases, but the role of Akt2 in cardiomyocytes is not fully understood. This study investigated the effect of Akt2 knockdown on tunicamycin (TM)-induced cytotoxicity in cardiomyocytes and the underlying mechanisms with a focus on the JNK-Wnt pathway. TM treatment significantly increased the expression of Akt2 at both mRNA and protein levels, which was shown to be mediated by the induction of reactive oxygen species (ROS). Knockdown of Akt2 expression via siRNA transfection markedly increased cell viability, decreased lactate dehydrogenase (LDH) release and reduced cell apoptosis after TM exposure. The results of western blot showed that downregulation of Akt2 also attenuated the TM-induced activation of the unfolded protein response (UPR) factors and ER stress associated pro-apoptotic proteins. In addition, Si-Akt2 transfection partially prevented the TM-induced decrease in nuclear localization of ß-catenin. By using the selective inhibitor SP-600,125 to inhibit JNK phosphorylation, we found that knockdown of Akt2-induced protection and inhibition of ER stress was mediated by reversing TM-induced decrease of Wnt through the JNK pathway. In summary, these data suggested that Akt2 play a pivotal role in regulating cardiomyocyte survival during ER stress by modulating the JNK-Wnt pathway.

The Toll-like receptor 4 antagonist TAK-242 protects against chronic pancreatitis in rats.

Chronic pancreatitis is a progressive disease characterized by irreversible morphological changes to the pancreas, typically causing pain and permanent loss of function. It is a poorly understood disease with the pathogenesis remaining unclear. The authors' previous data demonstrated that the inhibition of Toll­like receptor 4 (TLR4) using TLR4 antagonist kinase (TAK)­242 attenuates taurocholate­induced oxidative stress via the regulation of mitochondrial function in the pancreatic acinar cells of mice. In the present study, the effect of TAK­242 on trinitrobenzene sulfonic acid (TNBS)­induced chronic pancreatitis was investigated in rats. The results revealed that TAK­242 attenuated the severity of chronic pancreatic injury, and regulated extracellular matrix secretion and cellular immunity. In addition, TAK­242 treatment significantly decreased cell apoptosis, as evidenced by the reduction in Terminal deoxynucleotidyl transferase dUTP nick end labeling­positive cells in pancreas tissue sections, and also promoted cell proliferation in TNBS­treated animals. Furthermore, the results of the calibrated von Frey filament assay demonstrated that TAK­242 could prevent the pancreatitis­induced referred abdominal hypersensitivity. In summary, TAK­242 exhibits protective effects against TNBS­induced chronic pancreatitis and may be a potential therapeutic strategy for the treatment of patients with chronic pancreatitis.

Pregnancy complicated with agranulocytosis.

RATIONALE: Pregnancy is a complicated physiological process. Physiological leukocytosis often takes place and it is primarily related to the increased circulation of neutrophils, especially during the last trimester of pregnancy. Noncongenital agranulocytosis during pregnancy is rare and reported only occasionally, while in most of the cases, the agranulocytosis has already occurred prior to pregnancy or induced by identified factors such as antibiotics, antithyroid agents, or cytotoxic agents. Gestation-induced agranulocytosis has not been reported, so we present a case of gestation-induced agranulocytosis in this article. PATIENTS CONCERN: In this case, we present a Chinese woman (aged 25) in her 38th week of the first gestation who had the complication of agranulocytosis. No abnormality was detected in regular examinations before pregnancy and in the first trimester. Since the last trimester of pregnancy, the patient began to suffer from agranulocytosis and intermittent fever, the maximum being temperature 38.8°C. At admission, the neutrophil granulocytes were 0.17 × 10 L and the bone marrow biopsy showed that agranulocytosis was detected, but the levels of red blood cell and megalokaryocyte were normal. In addition, antinuclear antibodies were detected at a dilution of 1:40, but anti-dsDNA, antiphospholipid antibody, and neutrophil granulocyte antibody were negative. DIAGNOSES: The patient was empirically treated as having pneumonia. INTERVENTIONS: We tried to use granulocyte colony-stimulating factor, γ-globulin, glucocorticoids, antibiotics, and antifungi agents to treat the patient, but her symptoms were not alleviated until the patient had a cesarean section. OUTCOMES: After 24 hours of cesarean section, the temperature and neutrophil granulocyte returned to normal. After a year of follow-up, we found that the patient and the baby were healthy. LESSONS: Agranulocytosis during pregnancy seems to be associated with immunosuppression induced by immunoregulations and termination of pregnancy may be effective for refractory pregnancy complicated with agranulocytosis, but further studies are needed to confirm this.

The toll-like receptor 4 antagonist transforming growth factor-ß-activated kinase(TAK)-242 attenuates taurocholate-induced oxidative stress through regulating mitochondrial function in mice pancreatic acinar cells.

BACKGROUND: Acute pancreatitis (AP) is a commonly occurring and potentially life-threatening disease. Recently, toll-like receptor 4 (TLR4) has been considered as a new clue for studying the pathogenesis of AP due to its important role in inflammatory response cascade. MATERIALS AND METHODS: The aim of this study was to investigate the potential protective effect of transforming growth factor-ß-activated kinase (TAK)-242, a novel TLR4 antagonist, in taurocholate-treated mice pancreatic acinar cells. The protective effects were measured by cell viability, lactate dehydrogenase release and apoptosis, and oxidative stress was assayed by lipid peroxidation and oxidative enzyme activities. To determine the potential underlying mechanisms, mitochondrial cytochrome c release, swelling, and calcium buffering capacity were measured in isolated mitochondria, and mitochondrial biogenesis and expression of mitochondrial dynamic proteins were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. RESULTS: Treatment with 6-mM taurocholate significantly increased the expression of TLR4 at both mRNA and protein levels. TAK-242 markedly increased cell viability, decreased lactate dehydrogenase release, and inhibited apoptotic cell death as measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining in pancreatic acinar cells. These protective effects were accompanied by the suppressed lipid peroxidation and enhanced endogenous antioxidative enzyme activity. Using isolated and purified mitochondria from pancreatic acinar cells, we found that TAK-242 treatment also inhibited cytochrome c release into the cytoplasm, mitochondrial swelling, and decrease in mitochondrial Ca2+ buffering capacity after taurocholate exposure. In addition, TAK-242 significantly promoted mitochondrial biogenesis, as evidenced by increased mtDNA and upregulated mitochondrial transcription factors. The results of Western blot analysis showed that TAK-242 also differently regulated the expression of mitochondrial fusion and fission proteins. CONCLUSIONS: All these data strongly indicated that blocking TLR4 activity via TAK-242 exerts protective effects in an in vitro AP model, and it could be a possible strategy to improve clinical outcome in AP patients.

Preoxygenation using invasive ventilator in volume control mode in patients with emergency intubation can shorten the time of preoxygenation and improve the quality of preoxygenation: A retrospective study.

Preoxygenation can rapidly improve oxygenation and enhance the security of endotracheal intubation, so it is very essential before endotracheal intubation. The conventional preoxygenation method self-inflating bag (SIB) is not very effective in case of emergency. So our study aims to find a more effective method of preoxygenation in a critical situation.We retrospectively analyzed data of 105 patients in this study. A total of 49 patients with preoxygenation with invasive ventilator in volume control mode (VCM) and 56 patients with preoxygenation with SIB were included. No significant differences were detected in the baseline data of the 2 groups (P > 0.05). Time of preoxygenation (95%) was 174 (168-180) seconds in group VCM and 205 (199-212) seconds in group SIB (P < 0.05), and multifactor linear regression showed that its main risk factors were the methods of preoxygenation and PO2 before preoxygenation (P < 0.05). Immediate SPO2 after preoxygenation was 91 (89-92)% in group VCM and 85 (83-86)% in group SIB (P < 0.05). Total time of preoxygenation and intubation was 266 (252-280) seconds in group VCM and 318 (298-338) seconds in group SIB (P < 0.05). The 24-hour and overall survival rate in group SIB were lower than in group VCM (P > 0.05). Cox regression showed that SaO2 at 5 minutes after intubation was the major risk factor for the survival rate.Invasive ventilator with volume control mode can shorten the time of preoxygenation and improve the quality of preoxygenation in patients with emergency intubation and may be a better method of preoxygenation in a critical situation.