Treatment and prognostic risk factors for intracranial infection after craniocerebral surgery.

The objective of this study was to determine risk factors of pejorative evolution course in patients suffering from postoperative cranial infection. The data of patients who developed an intracranial infection after craniocerebral surgery in the neurosurgical intensive care unit of the First Affiliated Hospital of Nanjing Medical University in Nanjing, Jiangsu, China, from February 2018 to August 2019 were retrospectively analyzed. Logistic regression was used to analyze the factors influencing the prognosis of intracranial infection treatment. Sixty-four patients developed an infection after craniocerebral surgery, and 48 of them with negative CSF cultures received experimental anti-infectives. In 16 patients, cerebrospinal fluid culture showed pandrug-resistant pathogens, including 11 Acinetobacter baumannii (11), Klebsiella pneumoniae (3), Escherichia coli (1), and Candida glabrata (1). Nine patients received intraventricular or intrathecal injections of polymyxin B. The mean duration of infection treatment was 22.2 ± 9.9 days, and the clinical cure rate was 85.9% (55/64). Logistic multivariate regression analysis showed that inadequate CSF drainage (OR, 6.839; 95% CI, 1.130-41.383; P = 0.036) and infection with drug-resistant bacteria (OR, 24.241; 95% CI, 2.032-289.150; P = 0.012) were independent risk factors for postoperative intracranial infection. Intracranial infection with positive CSF culture and inadequate CSF drainage are factors contributing to the poor prognosis of intracranial infection. Moreover, early anti-infection treatment and adequate CSF drainage may improve patient outcomes. In particular, intraventricular or intrathecal injection of polymyxin B may be a safe and effective treatment strategy for MDR/XDR gram-negative bacilli infection.

Diversity of Circulating NKT Cells in Defense against Carbapenem-Resistant Klebsiella Pneumoniae Infection.

Nosocomial infection caused by carbapenem-resistant Klebsiella pneumonia (CRKP) infection has become a global public health problem. Human NK and NKT cells in peripheral immune responses are recognized as occupying a critical role in anti-bacterial immunity. Through performed scRNA-seq on serial peripheral blood samples from 3 patients with CRKP undergoing colonization, infection, and recovery conditions, we were able to described the immune responses of NK and NKT cells during CRKP infection and identified a mechanism that could contribute to CRKP clearance. The central player of CRKP infection process appears to be the NKT subset and CD56hiNKT subset which maintained immune competence during CRKP colonization. With time, CRKP leads to the loss of NK and CD160hiNKT cells in peripheral blood, resulting in suppressed immune responses and increased susceptibility to opportunistic infection. In summary, our study identified a possible mechanism for the CRKP invasion and to decipher the clues behind the host immune response that influences CRKP infection pathogenesis.

Sputum characteristics and airway clearance methods in patients with severe COVID-19.

Critically ill patients with coronavirus disease 2019 (COVID-19) have a high case fatality rate. Hence, controlling the disease progression of severely ill COVID-19 patients to avoid the development of severe-to-critical COVID-19 is the most important target of COVID-19 treatment. The latest autopsy results of COVID-19 patients have shown the presence of viscous secretions in the airways. However, no studies are available that specifically describe and analyze the sputum characteristics and the effects of various sputum drainage methods on the prognosis of COVID-19 patients. In our study, we found that elderly COVID-19 patients were more susceptible to progression to critical illness (P = .024) and were likely to have accompanying lymphopenia (P = .035) or increased neutrophil counts (P = .019). We observed that there was a higher proportion of patients with Grade 3 sticky sputum in the critically ill group than in the noncritically ill group (P = .026), suggesting that changes in sputum characteristics may be one of the early warning signs of critical COVID-19. In addition, we found that the application rates of large doses of ambroxol (P = .043) and prone-position drainage (P = .037) were relatively high in COVID-19 patients with good prognoses, suggesting that the early application of large doses of expectorant drugs and prone-position drainage in COVID-19 patients may avoid progression to critical illness and improve the prognosis.

Pulmonary arterial hypertension in critically ill elderly patients.

OBJECTIVE: To assess the incidence, possible risk factors and prognosis of pulmonary arterial hypertension (PAH) in critically ill elderly patients. METHODS: We selected 122 cases admitted to the ICU, ages 60-93 years old. An echocardiography examination was performed within four days after admission to the ICU. PAH is usually suspected if the patient's pulmonary artery systolic pressure ≥ 40 mmHg. We collected echocardiography data, relevant clinical data and routine laboratory data; we then used a statistical method to analyze the risk factors for PAH in critically ill elderly patients and examined its impact on the prognosis. RESULTS: Total 51 patients were diagnosed with PAH. The prevalence of critically ill elderly patients with PAH was 41.8%. The ANOVA analysis showed that if patients had COPD (P = 0.031) and/or respiratory failure (P = 0.021), they were more prone to PAH. An enlarged left atrium (P = 0.038) and/or right ventricle (P = 0.029), a declining left ventricle fractional shortening rate (P = 0.038), and an elevated amount of the brain natriuretic peptides (P = 0.046) were all associated with the occurrence of PAH. Multivariate regression analysis showed that the left atrial diameter (P = 0.045) was the risk factor in critically ill elderly patients with PAH. The 30-day mortality rate was 33.3% for elderly patients with PAH, which is statistically significant (P = 0.035) when compared with the mortality rate of patients with normal pulmonary artery pressure. Our multivariate regression analysis also showed that, for critically ill elderly patients admitted in the ICU, PAH (P = 0.039) is risk factor for increased mortality. CONCLUSIONS: A higher incidence of PAH occurs in critically ill elderly patients. PAH is more likely to occur in patients with an enlarged left atrium, and these problems adversely impact the prognosis.

Effects of bone marrow mesenchymal stem cells on the cardiac function and immune system of mice with endotoxemia.

The present study aimed to investigate the effects of bone marrow mesenchymal stem cells (MSCs) on the cardiac function and immune system of mice with endotoxemia. The mice were divided into the following groups: Control group, endotoxemia group, lipopolysaccharide (LPS) treatment group, LPS and MSC treatment group (LPS + MSC group) and MSC group. Following treatment with LPS, the cardiac function of the mice was examined at after 2, 6 and 24 h, and on day 7. An enzyme­linked immunofluorescent assay was used to analyze the serum and the levels of cytokines in the myocardium, and western blotting was used to investigate any changes in the levels of signaling proteins associated with the myocardium. A 3­(4,5­dimethyl­2­thiazolyl)­2,5­diphenyl­2H­tetrazolium bromide assay was used to investigate the growth rate of the splenic cells at after 24 h and on day 7, and the humoral immune function and phagocytosis of the macrophages in the mice were also examined. The cardiac function of the mice with endotoxemia declined, although this impairment was circumvented following treatment with MSCs. The levels of interleukin (IL)­1ß, IL­6, tumor necrosis factor­α and IL­10 in the serum and the myocardium increased following stimulation by LPS, although these declined as a result of MSC treatment. The expression levels of Toll­like receptor 4, p65­nuclear factor­κB and phosphorylated p38 in the mouse myocardium were enhanced following stimulation by LPS, which subsequently decreased as a result of MSC treatment. Compared with the control group, the growth rate of the splenic cells, humoral immune function and the level of phagocytosis of macrophages were all increased, although these parameters declined following treatment with MSCs. Taken together, the present study revealed that the MSCs inhibited the inflammatory reaction in the mice with endotoxemia, and improved cardiac function. By contrast, the cellular and humoral immunity were depressed, and phagocytosis of the macrophages, which were enhanced following simulation with LPS, were decreased following treatment with MSCs. However, no overexpression of the anti­inflammatory factor, IL­10, was observed. The present study hypothesized that MSCs exert a bifunctional role in endotoxemia, by inhibiting inflammatory factors, including IL­1 and IL­6, and inhibiting the compensatory expression of IL­10 following LPS stimulation. This avoids the possibility of excessive inhibition of immunological function, as this results in immunosuppression, and a higher ratio of IL­10 to TNF­α is indicative of a poor prognosis in patients with sepsis.

Iptakalim attenuates hypoxia-induced pulmonary arterial hypertension in rats by endothelial function protection.

The present study aimed to investigate the protective effects of iptakalim, an adenosine triphosphate (ATP)-sensitive potassium channel opener, on the inflammation of the pulmonary artery and endothelial cell injury in a hypoxia-induced pulmonary arterial hypertension (PAH) rat model. Ninety-six Sprague-Dawley rats were placed into normobaric hypoxia chambers for four weeks and were treated with iptakalim (1.5 mg/kg/day) or saline for 28 days. The right ventricle systolic pressures (RVSP) were measured and small pulmonary arterial morphological alterations were analyzed with hematoxylin and eosin staining. Enzyme-linked immunosorbent assay (ELISA) was performed to analyze the content of interleukin (IL)-1ß and IL-10. Immunohistochemical analysis for ED1(+) monocytes was performed to detect the inflammatory cells surrounding the pulmonary arterioles. Western blot analysis was performed to analyze the expression levels of platelet endothelial cell adhesion molecule-1 (PECAM-1) and endothelial nitric oxide synthase (eNOS) in the lung tissue. Alterations in small pulmonary arteriole morphology and the ultrastructure of pulmonary arterial endothelial cells were observed via light and transmission electron microscopy, respectively. Iptakalim significantly attenuated the increase in mean pulmonary artery pressure, RVSP, right ventricle to left ventricle plus septum ratio and small pulmonary artery wall remodeling in hypoxia-induced PAH rats. Iptakalim also prevented an increase in IL-1ß and a decrease in IL-10 in the peripheral blood and lung tissue, and alleviated inflammatory cell infiltration in hypoxia-induced PAH rats. Furthermore, iptakalim enhanced PECAM-1 and eNOS expression and prevented the endothelial cell injury induced by hypoxic stimuli. Iptakalim suppressed the pulmonary arteriole and systemic inflammatory responses and protected against the endothelial damage associated with the upregulation of PECAM-1 and eNOS, suggesting that iptakalim may represent a potential therapeutic agent for PAH.

Ruscogenin exerts beneficial effects on monocrotaline-induced pulmonary hypertension by inhibiting NF-κB expression.

This study aims to examine the effect of ruscogenin on pulmonary arterial hypertension (PAH) and to determine the mechanism underlying this effect. We isolated pulmonary vascular smooth muscle cells (PVSMCs) from the pulmonary artery of the rats; the PVSMCs were cultured in vitro and then were treated with platelet-derived growth factor (PDGF), PDGF + ruscogenin, or PDGF + ruscogenin + parthenolide. We randomized Sprague-Dawley rats into five groups as follows: control group, PAH group, low-dose group, medium-dose group, and high-dose group; the rats in the low-, medium-, and high-dose groups received the vehicle and ruscogenin 0.1, 0.4, and 0.7 mg/kg, respectively, from day 1 to day 21 after injection of monocrotaline (MCT). We measured the mean pulmonary arterial pressure (mPAP), right ventricular systolic pressure (RVSP), and medial wall thickness of the pulmonary artery (PAWT). We examined the levels of the nuclear factor kappa B (NF-κB) protein by using immunohistochemistry and western blot analysis, and the mRNA levels of NF-κB in PVSMCs were evaluated using real-time polymerase chain reaction (PCR). The mPAP, RVSP, and PAWT and the protein and mRNA levels of NF-κB were significantly higher in the PAH model group than in the control group (P < 0.05). Ruscogenin induced a significant dose-dependent decrease in the mPAP, RVSP, and PAWT and in the NF-κB expression in the PAH group (P < 0.05), which suggests that ruscogenin will also exert dose-dependent effects on MCT-induced PAH through the inhibition of NF-κB.

Paeoniflorin reduced BLP-induced inflammatory response by inhibiting the NF-κB signal transduction in pathway THP-1 cells.

Sepsis is a severe illness in which the bloodstream is overwhelmed by bacteria. Despite effective antibiotic treatment, the mortality of septic shock remains high. In this study, we examined a potential usage of paeoniflorin, anti-inflammatory component for the treatment of sepsis. We established an inflammatory cell line by stimulating human THP-1 cell line with bacterial lipoprotein (BLP), which resulted in an activation of nuclear factor κB (NF-κB) p65 dependent-signal pathway, and in consequence, an increase in tumor necrosis factor α (TNF-α) and interleukin (IL)-6 expression. With this model, we studied the effect of paeoniflorin on the expression of NF-κB and Toll-like receptor 2 (TLR2) mediated signal transduction. Our data indicated that paeoniflorin directly inhibited activation of NF-κB p65, thereby reduced the expression of TNF-α and IL-6 in the BLP stimulated THP-1 cells. Paeoniflorin was also found to inhibit IκB phosphorylation and degradation. However, no significant differences in TLR2 and myeloid differentiation factor 88 (MyD88) expression were observed; therefore, these signaling molecules may not have much anti-inflammatory effect in our cellular model. As such, our current study provided a molecular base for the potential use of paeoniflorin in therapeutic treatment of sepsis induced by bacterial lipoprotein.

Efficacy of linezolid on gram-positive bacterial infection in elderly patients and the risk factors associated with thrombocytopenia.

UNLABELLED: Objective : Linezolid is active against drug-resistant gram-positive bacteria. However, the efficacy and safety of linezolid in the treatment of the elderly have not been well characterized. The purpose of this study was to evaluate the efficacy of linezolid in the treatment of the elderly with gram-positive bacterial infection and to investigate the risk factors associated with the development of thrombocytopenia in these patients. METHODOLOGY: This was a retrospective analysis of 50 elderly patients who were treated with intravenous linezolid for gram-positive bacterial infection. Clinical data and bacteriological responses were assessed. Risk factors associated with thrombocytopenia in elderly patients were analyzed. RESULTS: The overall clinical cure rate of linezolid was 74%, and the bacteriological eradication rate was 69%. Thrombocytopenia occurred in 24 patients, and thrombocytopenia was associated with both the duration of treatment (P = 0.005) and the baseline platelet count (P = 0.042). Based on a logistic regression analysis, the baseline platelet count <200×10(9)/L (OR = 0.244; 95% CI = 0.068- 0.874; P = 0.030) was identified as the only significant risk factor for linezolid-associated thrombocytopenia in elderly patients. The mean platelet count decreased significantly from the 7(th) day of treatment, and decreased to the lowest value 1-2 days after the end of therapy. Conclusions : Linezolid is effective and safe for the elderly with gram-positive bacterial infections. Adverse effects such as thrombocytopenia are of greater concern. Platelet counts should be monitored in patients who are treated with linezolid and that measures should be taken in advance to avoid hemorrhagic tendencies.

Ruscogenin attenuates monocrotaline-induced pulmonary hypertension in rats.

Inflammation, endothelial dysfunction, and thrombosis contribute to the pathogenesis and development of human pulmonary arterial hypertension (PAH). The aim of this study was to investigate the effects of ruscogenin, a natural anti-inflammatory and anti-thrombotic agent, on the development of monocrotaline (MCT)-induced PAH in rats. Our results revealed that ruscogenin had favorable effects on hemodynamics and pulmonary vascular remodeling, preventing the development of PAH 3 weeks after MCT. In addition, ruscogenin resulted in markedly reduced expression of inflammatory cytokine and leukocyte infiltration via the inhibition of nuclear factor (NF)-κB activity in rat lungs. Ruscogenin also attenuated MCT-induced endothelial cell apoptosis in the remodeled pulmonary arterioles and rescued destruction of endothelial cell membrane proteins such as eNOS, caveolin-1, and CD31. Our findings suggest that ruscogenin might have therapeutic benefits for PAH patients.

NEDD9 rs760678 polymorphism and the risk of Alzheimer's disease: a meta-analysis.

The NEDD9 rs760678 polymorphism has been extensively investigated for association to Alzheimer's disease (AD), however, results of different studies have been inconsistent. The objective of this study is to assess the relationship of NEDD9 rs760678 polymorphism and AD risk by using meta-analysis. Systematic searches of electronic databases Pubmed and Embase, as well as hand searching of the references of identified articles were performed. Statistical analyses were performed using software Revman 4.2 and STATA 11.0. A total of 4436 cases and 4420 controls in 11 case-control studies were included. The results indicated that the homozygote GG had a 13% decreased risk of AD, when compared with the C allele carriers (CC+CG) (OR=0.87, 95%CI=0.77-0.99, P=0.04 for GG vs. CG+CC). In the subgroup analysis by ethnicity, significant decreased risk was associated with homozygote GG or G allele carriers in Caucasians (OR=0.84, 95%CI=0.74-0.96, P=0.008 for GG vs. CG+CC; OR=0.79, 95%CI=0.69-0.91, P=0.001 for GG vs. CC; OR=0.90, 95%CI=0.84-0.96, P=0.002 for G vs. C), but not in Asians. This meta-analysis suggests that the GG genotype of NEDD9 rs760678 polymorphism would be a protective factor for AD in Caucasians but not in Asians. To further evaluate the effect of gene-gene and gene-environmental interactions between NEDD9 rs760678 polymorphism and the risk of AD, more studies with larger number of subjects are required.

Nicorandil prevents right ventricular remodeling by inhibiting apoptosis and lowering pressure overload in rats with pulmonary arterial hypertension.

BACKGROUND: Most of the deaths among patients with severe pulmonary arterial hypertension (PAH) are caused by progressive right ventricular (RV) pathological remodeling, dysfunction, and failure. Nicorandil can inhibit the development of PAH by reducing pulmonary artery pressure and RV hypertrophy. However, whether nicorandil can inhibit apoptosis in RV cardiomyocytes and prevent RV remodeling has been unclear. METHODOLOGY/PRINCIPAL FINDINGS: RV remodeling was induced in rats by intraperitoneal injection of monocrotaline (MCT). RV systolic pressure (RVSP) was measured at the end of each week after MCT injection. Blood samples were drawn for brain natriuretic peptide (BNP) ELISA analysis. The hearts were excised for histopathological, ultrastructural, immunohistochemical, and Western blotting analyses. The MCT-injected rats exhibited greater mortality and less weight gain and showed significantly increased RVSP and RV hypertrophy during the second week. These worsened during the third week. MCT injection for three weeks caused pathological RV remodeling, characterized by hypertrophy, fibrosis, dysfunction, and RV mitochondrial impairment, as indicated by increased levels of apoptosis. Nicorandil improved survival, weight gain, and RV function, ameliorated RV pressure overload, and prevented maladaptive RV remodeling in PAH rats. Nicorandil also reduced the number of apoptotic cardiomyocytes, with a concomitant increase in Bcl-2/Bax ratio. 5-hydroxydecanoate (5-HD) reversed these beneficial effects of nicorandil in MCT-injected rats. CONCLUSIONS/SIGNIFICANCE: Nicorandil inhibits PAH-induced RV remodeling in rats not only by reducing RV pressure overload but also by inhibiting apoptosis in cardiomyocytes through the activation of mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels. The use of a mitoK(ATP) channel opener such as nicorandil for PAH-associated RV remodeling and dysfunction may represent a new therapeutic strategy for the amelioration of RV remodeling during the early stages of PAH.

Association of polymorphism of DNA repair gene XRCC1 with sporadic late-onset Alzheimer's disease and age of onset in elderly Han Chinese.

Alzheimer's disease (AD) is characterized by the presence of beta-amyloid plaques, neurofibrillary tangles and extensive neuronal loss. There is evidence indicating that the increased DNA damages may contribute to neuronal loss in AD. Recently, it has been shown that the capacity of some types of DNA repair is impaired in the neurons of AD patients. A functional polymorphism (Arg194Trp) of X-ray repair cross-complementing group 1 (XRCC1) gene may be associated with the repair efficiency of DNA damage which may have a role in AD. Therefore, XRCC1 Arg194Trp polymorphism may be a good candidate for genetic risk analysis in AD. A case-control study from Turkey found that XRCC1 194Trp was associated with late-onset AD (LOAD). In order to determine whether the XRCC1 gene Arg194Trp polymorphism contributes to the risk for LOAD in elderly Han Chinese, we have investigated it in 212 sporadic LOAD patients and 203 healthy controls from Chinese. No significantly increased risk of LOAD in the carriers of XRCC1 194Trp allele (OR=1.04, 95% CI 0.70-1.52, P=0.860) was observed. As expected, Apolipoprotein (APOE) epsilon4 allele significantly increased the risk of LOAD (OR=2.95, 95% CI 1.90-4.58, P<0.001), while APOE epsilon2 allele significantly decreased the risk of LOAD (OR=0.13, 95% CI 0.08-0.24, P<0.001). After stratifying by APOE epsilon4 status, no increased LOAD risks associated with the XRCC1 194Trp allele carriers were observed. Our findings suggest that it is unlikely that the XRCC1 Arg194Trp polymorphism plays a major role in the pathogenesis of LOAD in elderly Han Chinese and does not support the previous findings that 194Trp allele confers an increased risk for LOAD.