Exploration of neuron heterogeneity in human heart failure with dilated cardiomyopathy through single-cell RNA sequencing analysis.

OBJECTIVE: We aimed to explore the heterogeneity of neurons in heart failure with dilated cardiomyopathy (DCM). METHODS: Single-cell RNA sequencing (scRNA-seq) data of patients with DCM and chronic heart failure and healthy samples from GSE183852 dataset were downloaded from NCBI Gene Expression Omnibus, in which neuron data were extracted for investigation. Cell clustering analysis, differential expression analysis, trajectory analysis, and cell communication analysis were performed, and highly expressed genes in neurons from patients were used to construct a protein-protein interaction (PPI) network and validated by GSE120895 dataset. RESULTS: Neurons were divided into six subclusters involved in various biological processes and each subcluster owned its specific cell communication pathways. Neurons were differentiated into two branches along the pseudotime, one of which was differentiated into mature neurons, whereas another tended to be involved in the immune and inflammation response. Genes exhibited branch-specific differential expression patterns. FLNA, ITGA6, ITGA1, and MDK interacted more with other gene-product proteins in the PPI network. The differential expression of FLNA between DCM and control was validated. CONCLUSION: Neurons have significant heterogeneity in heart failure with DCM, and may be involved in the immune and inflammation response to heart failure.

Ghrelin attenuate cerebral microvascular leakage by regulating inflammation and apoptosis potentially via a p38 MAPK-JNK dependent pathway.

Ghrelin is a peptide hormone with strong anti-inflammatory properties. In fact, Ghrelin was reported to improve endothelial dysfunction caused by excessive fat. However, its role in preserving the integrity of brain microvascular, under conditions of lipid dysregulation and inflammation, is not known. The objective of this study is to characterize the role of Ghrelin in the protection of cerebral microvascular integrity, during atherosclerosis, and uncover its underlying molecular mechanism. Our results demonstrated that an atherosclerotic condition, brought on by a high fat diet (HFD), can produce massive increases in serum inflammatory factors, blood lipids, cerebral microvascular leakage, and activation of the p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) (p38 MAPK-JNK) pathway. It also produced significantly damaged pericytes morphology, resulting in pericyte decrease. Ghrelin treatment, on the other hand, protected against cerebral microvascular leakage and pericytes damage. Ghrelin effectively downregulated the expression of pro-inflammatory cytokines, and it also suppressed the p38 MAPK-JNK signaling pathway. Additionally, in isolated mouse cerebral microvascular pericytes, ox-LDL lead to increased apoptosis and secretion of inflammatory factors, along with an elevation in phosphorylated p38 MAPK-JNK proteins. Alternately, Ghrelin administration markedly lowered expression of inflammatory factors, suppressed the p38 MAPK-JNK signaling path, and halted cell apoptosis. However, pretreatment of Hesperetin, a p38 MAPK-JNK agonist, abrogated the Ghrelin-mediated suppression of inflammation and apoptosis in pericytes. Taken together, these results suggest that Ghrelin restored cerebral microvascular integrity and reduced vascular leakage in atherosclerosis mice, in part, by its regulation of inflammatory and apoptotic signaling pathways in pericytes.

Antibiotics De-Escalation in the Treatment of Ventilator-Associated Pneumonia in Trauma Patients: A Retrospective Study on Propensity Score Matching Method.

BACKGROUND: Antimicrobial de-escalation refers to starting the antimicrobial treatment with broad-spectrum antibiotics, followed by narrowing the drug spectrum according to culture results. The present study evaluated the effect of de-escalation on ventilator-associated pneumonia (VAP) in trauma patients. METHODS: This retrospective study was conducted on trauma patients with VAP, who received de-escalation therapy (de-escalation group) or non-de-escalation therapy (non-de-escalation group). Propensity score matching method was used to balance the baseline characteristics between both groups. The 28-day mortality, length of hospitalization and Intensive Care Unit stay, and expense of antibiotics and hospitalization between both groups were compared. Multivariable analysis explored the factors that influenced the 28-day mortality and implementation of de-escalation. RESULTS: Among the 156 patients, 62 patients received de-escalation therapy and 94 patients received non-de-escalation therapy. No significant difference was observed in 28-day mortality between both groups (28.6% vs. 23.8%, P = 0.620). The duration of antibiotics treatment in the de-escalation group was shorter than that in the non-de-escalation group (11 [8-13] vs. 14 [8-19] days, P = 0.045). The expenses of antibiotics and hospitalization in de-escalation group were significantly lower than that in the non-de-escalation group (6430 ± 2730 vs. 7618 ± 2568 RMB Yuan, P = 0.043 and 19,173 ± 16,861 vs. 24,184 ± 12,039 RMB Yuan, P = 0.024, respectively). Multivariate analysis showed that high Acute Physiology and Chronic Health Evaluation II (APACHE II) score, high injury severity score, multi-drug resistant (MDR) infection, and inappropriate initial antibiotics were associated with patients' 28-day mortality, while high APACHE II score, MDR infection and inappropriate initial antibiotics were independent factors that prevented the implementation of de-escalation. CONCLUSIONS: De-escalation strategy in the treatment of trauma patients with VAP could reduce the duration of antibiotics treatments and expense of hospitalization, without increasing the 28-day mortality and MDR infection.

Effect of Candida albicans on Intestinal Ischemia-reperfusion Injury in Rats.

BACKGROUND: Inflammation is supposed to play a key role in the pathophysiological processes of intestinal ischemia-reperfusion injury (IIRI), and Candida albicans in human gut commonly elevates inflammatory cytokines in intestinal mucosa. This study aimed to explore the effect of C. albicans on IIRI. METHODS: Fifty female Wistar rats were divided into five groups according to the status of C. albicans infection and IIRI operation: group blank and sham; group blank and IIRI; group cefoperazone plus IIRI; group C. albicans plus cefoperazone and IIRI (CCI); and group C. albicans plus cefoperazone and sham. The levels of inflammatory factors tumor necrosis factor (TNF)-µ, interleukin (IL)-6, IL-1ß, and diamine oxidase (DAO) measured by enzyme-linked immunosorbent assay were used to evaluate the inflammation reactivity as well as the integrity of small intestine. Histological scores were used to assess the mucosal damage, and the C. albicans blood translocation was detected to judge the permeability of intestinal mucosal barrier. RESULTS: The levels of inflammatory factors TNF-µ, IL-6, and IL-1ß in serum and intestine were higher in rats undergone both C. albicans infection and IIRI operation compared with rats in other groups. The levels of DAO (serum: 44.13 ± 4.30 pg/ml, intestine: 346.21 ± 37.03 pg/g) and Chiu scores (3.41 ± 1.09) which reflected intestinal mucosal disruption were highest in group CCI after the operation. The number of C. albicans translocated into blood was most in group CCI ([33.80 ± 6.60] ×102 colony forming unit (CFU)/ml). CONCLUSION: Intestinal C. albicans infection worsened the IIRI-induced disruption of intestinal mucosal barrier and facilitated the subsequent C. albicans translocation and dissemination.

[Lipids disorder, macrovascular diseases, and insulin resistance in Chinese diabetic patients].

OBJECTIVE: To investigate the types of lipid disorder and its relationship with macrovascular diseases and insulin resistance in Chinese diabetic patients. METHODS: 2,430 diabetic patients finished the diabetes complications assessment and were surveyed on their blood lipids, insulin level and macrovascular diseases. The insulin resistance (HOMA-IR) was calculated based on HOMA model. RESULTS: Prevalence of lipids disorder was as high as 63.8% in this group, including 23.9% with both hypercholesterolemia and hypertriglyceridemia (HY-C-T), 16.1% with hypercholesterolemia only (HY-C), 15.0% with hypertriglyceridemia only (HY-T), 5.5% with lower HDL level (L-HDL), 3.3% with hypercholesterolemia, hypertriglyceridemia and lower HDL level together. Compared with the patients with normal lipid level (control group), no duration differences existed among these groups. There were more female patients in HY-C and HY-C-T groups. BMI and WHR were higher in all groups with lipid disorder except in HY-C group. Macrovascular diseases were more common in HY-C-T patients than in control group (33.6% vs 24.0%, P < 0.001). Average blood pressure and the prevalence of hypertension were significantly higher in HY-C-T, HY-C, HY-T groups than in control group (139/79, 138/76, 134/77 vs. 132/75 mmHg; 53.2%, 50.1%, 46.2% vs. 39.2%). Fasting insulin level was significantly higher in HY-C-T and HY-C-T-L-LDL groups than in controls. Insulin resistance was more severe in all patients with lipid disorder except in L-HDL group, particularly in the HY-C-T-L-HDL group. CONCLUSIONS: (1) BMI, WHR increased significantly with the severity of lipid disorder. (2) Nearly two thirds of Chinese diabetic patients have lipid disorder, which is the strong risk factor of macrovascular diseases and aggravates insulin resistance. (3) There was severe insulin resistance in patients with hypertriglyceridemia or with hypertriglyceridemia plus other lipid disorder.