Background: Pulmonary sepsis and abdominal sepsis have pathophysiologically distinct phenotypes. This study aimed to compare their clinical characteristics and predictors of mortality. Methods: In this multicenter retrospective trial, 1,359 adult patients who fulfilled the Sepsis-3 criteria were enrolled and classified into the pulmonary sepsis or abdominal sepsis groups. Plasma presepsin was measured, and the scores of Acute Physiology and Chronic Health Evaluation (APACHE) II, Mortality in Emergency Department Sepsis (MEDS), and Simplified Acute Physiology Score (SAPS) II were calculated at enrollment. Data on 28-day mortality were collected for all patients. Results: Compared with patients with abdominal sepsis (n = 464), patients with pulmonary sepsis (n = 895) had higher 28-day mortality rate, illness severity scores, incidence of shock and acute kidney injury, and hospitalization costs. Lactate level and APACHE II and MEDS scores were independently associated with 28-day mortality in both sepsis types. Independent predictors of 28-day mortality included PaO 2 /FIO 2 ratio (hazard ratio [HR], 0.998; P < 0.001) and acute kidney injury (HR, 1.312; P = 0.039) in pulmonary sepsis, and SAPS II (HR, 1.037; P = 0.017) in abdominal sepsis. A model that combined APACHE II score, lactate, and MEDS score or SAPS II score had the best area under the receiver operating characteristic curve in predicting mortality in patients with pulmonary sepsis or abdominal sepsis, respectively. Interaction term analysis confirmed the association between 28-day mortality and lactate, APACHE II score, MEDS score, SAPS II score, and shock according to the sepsis subgroups. The mortality of patients with pulmonary sepsis was higher than that of patients with abdominal sepsis among patients without shock (32.9% vs. 8.8%; P < 0.001) but not among patients with shock (63.7 vs. 48.4%; P = 0.118). Conclusions: Patients with pulmonary sepsis had higher 28-day mortality than patients with abdominal sepsis. The study identified sepsis subgroup-specific mortality predictors. Shock had a larger effect on mortality in patients with abdominal sepsis than in those with pulmonary sepsis.
Lead is a heavy metal commonly found in the environment with known neurotoxicity, hematological and other toxicities. It has been found that lead exposure can disturb partial metal regulatory function in the blood-CSF barrier (BCB). Copper, which play an important role in maintaining normal brain function, can accumulate in brain after lead exposure. The studies of Alzheimer's disease (AD) indicated that abnormal copper homeostasis in cerebrospinal fluid (CSF) may be involved in the pathogenesis. However, the mechanism of copper disturbance in the brain caused by lead is still unknown. This study was designed to investigate copper clearance by the BCB in central nervous system after lead exposure, with focus on copper transporter protein CTR1/ATP7A. Inductively coupled plasma mass spectrometry (ICP-MS) and principal component analysis (PCA) were used to identify the changes of heavy metal level in hippocampus and CSF after lead exposure. It was found that the change in copper level was most pronounced in the brain between 3 to 12 weeks post lead exposure. Ventriculo-cisternal (VC) perfusion in Sprague Dawley (SD) rat suggested that the ability of BCB to deliver copper from the CSF to blood was decreased after lead exposure. Confocal microscope showed evidence of the presence of excess copper in the choroid plexus cells leading to CTR1/ATP7A shifting toward the apical microvilli facing the CSF after lead exposure. Finally, transmission electron microscopy (TEM) was used for observation of the microstructure of choroid plexus showed altered mitochondrial morphology with decreased microvilli after lead exposure. Our data suggested that lead exposure may alter BCB cellular microscopic structure and its copper transport, clearance function that might further cause brain injury.
Background: Abnormal lipid metabolism and inflammation play critical roles in the initiation and progression of atherosclerosis and its associated complications, including coronary artery disease (CAD) and acute myocardial infarction (AMI). Autophagic-lysosomal system is involved in many physiological processes, such as lipid metabolism and inflammation. TFEB, a master regulator of the system, coordinates the expression of lysosomal hydrolases, lysosomal membrane proteins, and autophagic proteins. Altered level of TFEB gene expression and subsequent changes of autophagic-lysosomal system may be involved in the onset of CAD and AMI.Methods: In this study, the promoter of the TFEB gene was genetically and functionally analyzed in AMI patients (n=352) and ethnic-matched healthy controls (n=337).Results: A total of fifteen genetic variants, including eight single nucleotide polymorphisms (SNPs), were identified in the participants. Two novel genetic variants and four SNPs were only identified in six AMI patients, and significantly altered the transcriptional activity of the TFEB gene in cultured cells. Further electrophoretic mobility shift assay revealed that two genetic variants (g.41737144A>G and g.41736544C>T) and two SNPs [g.41737274T>C (rs533895008) and g.41736987C>T (rs760293138)] evidently affected the binding of transcription factors.Conclusions: Our findings suggested that the genetic variants in TFEB gene promoter may change TFEB levels, contributing to AMI as a low-frequency risk factor.
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