Hepatic IRE1α-XBP1 signaling promotes GDF15-mediated anorexia and body weight loss in chemotherapy.

Platinum-based chemotherapy drugs can lead to the development of anorexia, a detrimental effect on the overall health of cancer patients. However, managing chemotherapy-induced anorexia and subsequent weight loss remains challenging due to limited effective therapeutic strategies. Growth differentiation factor 15 (GDF15) has recently gained significant attention in the context of chemotherapy-induced anorexia. Here, we report that hepatic GDF15 plays a crucial role in regulating body weight in response to chemo drugs cisplatin and doxorubicin. Cisplatin and doxorubicin treatments induce hepatic Gdf15 expression and elevate circulating GDF15 levels, leading to hunger suppression and subsequent weight loss. Mechanistically, selective activation by chemotherapy of hepatic IRE1α-XBP1 pathway of the unfolded protein response (UPR) upregulates Gdf15 expression. Genetic and pharmacological inactivation of IRE1α is sufficient to ameliorate chemotherapy-induced anorexia and body weight loss. These results identify hepatic IRE1α as a molecular driver of GDF15-mediated anorexia and suggest that blocking IRE1α RNase activity offers a therapeutic strategy to alleviate the adverse anorexia effects in chemotherapy.

A protein-based prognostic model for pancreatic ductal adenocarcinoma: Construction and validation.

BACKGROUND: Probing relevant proteomic biomarkers may facilitate effective pancreatic adenocarcinoma (PDAC) diagnosis, treatment and prevention. Here, we developed a protein-based prognostic model for PDAC by using relevant proteomic biomarkers data from The Cancer Genome Atlas (TCGA). METHODS: We obtained PDAC's proteomic and clinical data from TCGA and used various analytical tools to identify differentially expressed proteins between normal and cancer tissues. We constructed our protein-based prognostic model and confirmed its accuracy using receiver operating characteristic curve and Kaplan-Meier survival analyses. We elucidated clinical factor-signature protein correlations by clinical correlation assessments and protein coexpression networks. We also used immunohistochemistry (protein expression assessment), Gene Set Enrichment Analysis (protein role identification) and CIBERSORT (infiltrating immune cell distribution assessment). RESULTS: CIITA, BRAF_pS445, AR, YTHDF2, IGFBP2 and CDK1_pT14 were identified as PDAC-associated prognostic proteins. All risk scores calculated using our model provided 1-, 3-, 5-year survival probability at 70 % accuracy. The reliability of our model was validated by the GEO as well. In high- and low-risk groups, age, sex, T- and N- stage disparities were significant, and prognostic and coexpressed proteins correlated. PDAC tissues demonstrated significant CDK1_pT14 overexpression but significant BRAF_pS445, YTHDF2, and IGFBP2 underexpression. Downstream proteins of BRAF were validated by IHC. Low-risk tissues demonstrated more naïve B cells, eosinophils, activated NK cells and regulatory T cells, whereas high-risk tissues demonstrated more activated memory T cells, monocytes, neutrophils, dendritic cells and resting NK cells. CONCLUSIONS: Our protein-based prognostic model for PDAC, along with six signature proteins, might aid in predicting PDAC prognosis and therapeutic targets.

Plasma cell-free DNA promise monitoring and tissue injury assessment of COVID-19.

Coronavirus 2019 (COVID-19) is a complex disease that affects billions of people worldwide. Currently, effective etiological treatment of COVID-19 is still lacking; COVID-19 also causes damages to various organs that affects therapeutics and mortality of the patients. Surveillance of the treatment responses and organ injury assessment of COVID-19 patients are of high clinical value. In this study, we investigated the characteristic fragmentation patterns and explored the potential in tissue injury assessment of plasma cell-free DNA in COVID-19 patients. Through recruitment of 37 COVID-19 patients, 32 controls and analysis of 208 blood samples upon diagnosis and during treatment, we report gross abnormalities in cfDNA of COVID-19 patients, including elevated GC content, altered molecule size and end motif patterns. More importantly, such cfDNA fragmentation characteristics reflect patient-specific physiological changes during treatment. Further analysis on cfDNA tissue-of-origin tracing reveals frequent tissue injuries in COVID-19 patients, which is supported by clinical diagnoses. Hence, our work demonstrates and extends the translational merit of cfDNA fragmentation pattern as valuable analyte for effective treatment monitoring, as well as tissue injury assessment in COVID-19.

Different Doping of VSe2 Monolayers as Adsorbent and Gas Sensing Material for Scavenging and Detecting SF6 Decomposed Species.

The application of intrinsic and transition metals (TM)-doped VSe2 monolayers for the detection of faulty gases in SF6 electrical insulated equipment is investigated based on first-principles calculations. The electron density difference, density of state, and adsorption energy are analyzed to further clarify the reaction mechanism. The results show that the intrinsic VSe2 monolayer has weak adsorption performance for SO2 and SOF2 molecules, but the adsorption properties of the system are significantly improved after doping TM atoms. Among them, the TM-doped VSe2 monolayer has better sensing performance for SO2 than for SOF2 molecules. Furthermore, the modulating effect of biaxial strain on the gas-sensitive properties of TM-doped VSe2 system is also analyzed. Finally, the recovery time of the gas molecules on the solid adsorbent is evaluated. The results confirm that the TM-doped VSe2 monolayer can be used as a novel sensing material or scavenger to ensure the normal operation of SF6 electrical insulated equipment. This will provide a prospective insight for experimenters to implement VSe2-based sensing materials or scavengers.

Changes of blood gas analysis in moderate-to-severe acute respiratory distress syndrome patients during long-term prone position ventilation: a retrospective cohort study.

Background: Prone position ventilation (PPV) has been recommended for patients with acute respiratory distress syndrome (ARDS) to improve oxygenation. However, whether prolonged prone ventilation will aggravate hyperoxia and whether abdominal compression will aggravate permissive hypercapnia acidosis are topics of concern. We carried out a retrospective analysis to investigate the issues above. Methods: Clinical data were collected from 97 moderate-to-severe ARDS patients who received PPV as part of their treatment in the intensive care unit (ICU) of the First Affiliated Hospital of Guangzhou Medical University from November 2015 to May 2021. We collected arterial blood gas of patients according to the 3 periods: supine position ventilation (SPV), PPV early stage (within 4 hours), and PPV middle and late stage (6 hours or later). We established a linear mixed-effects models with "body position changes, times of PPV, gender, age, baseline SOFA, and baseline APACHE II" as fixed effects, and individual and the number of prone positions as random intercept and random slope to investigate the effect of body position changes on blood gas analysis. Results: Among the 97 patients received PPV included, 51 were ICU survivors. Arterial partial pressure of oxygen (PaO2) and PaO2/fraction of inspired oxygen (FiO2) ratio were significantly higher at the early, middle and late stages of PPV than those in SPV [PFR (mmHg): 158 (118.00, 203.00) vs. 161 (129.00, 202.75) vs. 123 (91.75, 163.00), P<0.05]. Despite the synchronized reduction of FiO2, the incidence of hyperoxia in the prone position was still significantly higher than that in the supine position [hyperoxia (%):33.33 vs. 33.56 vs. 12.42, P<0.05]; there was no significant change in arterial carbon dioxide partial pressure (PaCO2) at each stage of PPV, but there was a significant increase in PH at PPV middle and late stages than those at early stage [PH: 7.39 (7.34, 7.42) vs. 7.37 (7.31, 7.41), P<0.05]. Conclusions: Although PPV improves the patients' oxygenation, the associated incidence of hyperoxia exceeds 33%. Down-regulate FiO2 more sharply after PPV is necessary, if oxygenation conditions permit. PPV may alleviate the acidosis associated with permissive hypercapnia in ARDS patients treated with lung protective ventilation strategy (LPVS).

Electrical impedance tomography for titration of positive end-expiratory pressure in acute respiratory distress syndrome patients with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of most common comorbidities in acute respiratory distress syndrome (ARDS). There are few specific studies on the appropriate ventilation strategy for patients with ARDS comorbid with COPD, especially regarding on positive end-expiratory pressure (PEEP) titration. METHODS: To compare the respiratory mechanics in mechanical ventilated ARDS patients with or without COPD and to determine whether titration of PEEP based on electrical impedance tomography (EIT) is superior to the ARDSnet protocol. This is a single center, perspective, repeated measure study. ARDS patients requiring mechanical ventilation who were admitted to the intensive care unit between August 2017 and December 2020 were included. ARDS patients were divided according to whether they had COPD into a COPD group and a non-COPD group. Respiratory mechanics, gas exchange, and hemodynamics during ventilation were compared between the groups according to whether the PEEP level was titrated by EIT or the ARDSnet protocol. RESULTS: A total of twenty-seven ARDS patients including 14 comorbid with and 13 without COPD who met the study eligibility criteria were recruited. The PEEP levels titrated by EIT and the ARDSnet protocol were lower in the COPD group than in the non-COPD group (6.93 ± 1.69 cm H2O vs. 12.15 ± 2.40 cm H2O, P < 0.001 and 10.43 ± 1.20 cm H2O vs. 14.0 ± 3.0 cm H2O, P < 0.001, respectively). In the COPD group, the PEEP level titrated by EIT was lower than that titrated by the ARDSnet protocol (6.93 ± 1.69 cm H2O vs. 10.43 ± 1.20 cm H2O, P < 0.001), as was the global inhomogeneity (GI) index (0.397 ± 0.040 vs. 0.446 ± 0.052, P = 0.001), plateau airway pressure (16.50 ± 4.35 cm H2O vs. 20.93 ± 5.37 cm H2O, P = 0.001), dead space ventilation ratio (48.29 ± 6.78% vs. 55.14 ± 8.85%, P < 0.001), ventilation ratio (1.63 ± 0.33 vs. 1.87 ± 0.33, P < 0.001), and mechanical power (13.92 ± 2.18 J/min vs. 15.87 ± 2.53 J/min, P < 0.001). The cardiac index was higher when PEEP was treated by EIT than when it was titrated by the ARDSnet protocol (3.41 ± 0.50 L/min/m2 vs. 3.02 ± 0.43 L/min/m2, P < 0.001), as was oxygen delivery (466.40 ± 71.08 mL/min/m2 vs. 411.10 ± 69.71 mL/min/m2, P = 0.001). CONCLUSION: Titrated PEEP levels were lower in patients with ARDS with COPD than in ARDS patients without COPD. In ARDS patient comorbid with COPD, application of PEEP titrated by EIT was lower than those titrated by the ARDSnet protocol, which contributed to improvements in the ventilation ratio, mechanical energy, cardiac index, and oxygen delivery with less of an adverse impact on hemodynamics.

Rational Design of SnO2 Hollow Microspheres Functionalized with Derivatives of Pt Loaded MOFs for Superior Formaldehyde Detection.

In this work, SnO2 hollow microspheres functionalized with different incorporated amounts of Pt@Co3O4 complex catalyst were innovatively designed by using an MOF template. The results show that sensor based on the optimal incorporated amount of Pt@Co3O4 not only greatly enhances the response value of SnO2 to formaldehyde (Rair/Rformaldehyde = 4240 toward 100 ppm) but also decreases the low detection limit (50 ppb), which is quite outstanding compared with other SnO2-based formaldehyde sensors. Further analysis proves that the content of oxygen vacancy and chemisorbed oxygen and the catalytic effect of ultra-small Pt play the key roles in improving the formaldehyde sensing performance. Meanwhile, this present work demonstrates that oxide semiconductors functionalized with the derivatives of MOF templated catalysts may lead to the discovery of new material systems with outstanding sensing performance.

A Low-Producing Haplotype of Interleukin-6 Disrupting CTCF Binding Is Protective against Severe COVID-19.

Interleukin6 (IL-6) is a key driver of hyperinflammation in COVID-19, and its level strongly correlates with disease progression. To investigate whether variability in COVID-19 severity partially results from differential IL-6 expression, functional single-nucleotide polymorphisms (SNPs) of IL-6 were determined in Chinese COVID-19 patients with mild or severe illness. An Asian-common IL-6 haplotype defined by promoter SNP rs1800796 and intronic SNPs rs1524107 and rs2066992 correlated with COVID-19 severity. Homozygote carriers of C-T-T variant haplotype were at lower risk of developing severe symptoms (odds ratio, 0.256; 95% confidence interval, 0.088 to 0.739; P = 0.007). This protective haplotype was associated with lower levels of IL-6 and its antisense long noncoding RNA IL-6-AS1 by cis-expression quantitative trait loci analysis. The differences in expression resulted from the disturbance of stimulus-dependent bidirectional transcription of the IL-6/IL-6-AS1 locus by the polymorphisms. The protective rs2066992-T allele disrupted a conserved CTCF-binding locus at the enhancer elements of IL-6-AS1, which transcribed antisense to IL-6 and induces IL-6 expression in inflammatory responses. As a result, carriers of the protective allele had significantly reduced IL-6-AS1 expression and attenuated IL-6 induction in response to acute inflammatory stimuli and viral infection. Intriguingly, this low-producing variant that is endemic to present-day Asia was found in early humans who had inhabited mainland Asia since ∼40,000 years ago but not in other ancient humans, such as Neanderthals and Denisovans. The present study suggests that an individual's IL-6 genotype underlies COVID-19 outcome and may be used to guide IL-6 blockade therapy in Asian patients. IMPORTANCE Overproduction of cytokine interleukin-6 (IL-6) is a hallmark of severe COVID-19 and is believed to play a critical role in exacerbating the excessive inflammatory response. Polymorphisms in IL-6 account for the variability of IL-6 expression and disparities in infectious diseases, but its contribution to the clinical presentation of COVID-19 has not been reported. Here, we investigated IL-6 polymorphisms in severe and mild cases of COVID-19 in a Chinese population. The variant haplotype C-T-T, represented by rs1800796, rs1524107, and rs2066992 at the IL-6 locus, was reduced in patients with severe illness; in contrast, carriers of the wild-type haplotype G-C-G had higher risk of severe illness. Mechanistically, the protective variant haplotype lost CTCF binding at the IL-6 intron and responded poorly to inflammatory stimuli, which may protect the carriers from hyperinflammation in response to acute SARS-CoV-2 infection. These results point out the possibility that IL-6 genotypes underlie the differential viral virulence during the outbreak of COVID-19. The risk loci we identified may serve as a genetic marker to screen high-risk COVID-19 patients.

Independent risk factors of hypoxemia in patients after surgery with acute type A aortic dissection.

BACKGROUND: This study aimed to investigate independent risk factors of postoperative hypoxemia in patients with acute type A aortic dissection (ATAAD). METHODS: A single-center retrospective study was conducted with enrolled 75 ATAAD patients following surgery, which were stratified into three groups on the basis of the postoperative PaO2/FiO2 ratio: severe hypoxemia group (PaO2/FiO2 ratio ≤100 mmHg); moderate hypoxemia group (100 mmHg < PaO2/FiO2 ratio ≤200 mmHg); and non-hypoxemia group (PaO2/FiO2 ratio >200 mmHg). The patient's demography, perioperative laboratory results, operative details, clinical outcomes were collected and analyzed. Univariable and multivariable analyses were performed and logistic regression model was established. RESULTS: The incidence of postoperative severe hypoxemia and hypoxemia was 32% and 52%, respectively. Among the three groups, severe hypoxemia group exhibited a high significance of body mass index (BMI) and preoperative white blood cell (WBC) and main distribution of hypertension; meanwhile, Marfan syndrome was mainly distributed in non-hypoxemia group. On intensive care unit (ICU) admission, severe hypoxemia group exhibited a high significance of Acute Physiology and Chronic Health Evaluation (APACHE II) score of postoperative patients, and more patients would present shock. Moreover, severe hypoxemia group patients had a higher incidence of postoperative acute kidney injury (AKI) and usage of renal replacement therapy, longer length of stay (LOS) of ICU, and shorter 28 days ventilator-free days (VFDs). CONCLUSIONS: The incidence of postoperative hypoxemia was high in ATAAD patients owing to comprehensive high-risk factors. Besides, postoperative complications negatively impacted their clinical outcomes.

Acute Respiratory Distress Syndrome Caused by Human Adenovirus in Adults: A Prospective Observational Study in Guangdong, China.

BACKGROUND: Viral causes of acute respiratory distress syndrome (ARDS) are mostly limited to influenza. However, adenovirus has been emerging as a cause of ARDS with a high mortality rate and described in adults are rare. METHODS: We conducted a prospective, single-center observational study of viral pneumonia with ARDS and confirmed adenovirus-associated ARDS in adults at our quaternary referral institution between March 2019 and June 2020. We prospectively analyzed clinical characteristics, laboratory test results, radiological characteristics, viral load from nasopharyngeal swabs and endotracheal aspirates, treatments, and outcomes for the study participants. RESULTS: The study enrolled 143 ARDS patients, including 47 patients with viral pneumonia-related ARDS, among which there were 14 adenovirus-associated ARDS patients, which accounted for 29.79% of the viral pneumonia-related ARDS cases. Among the adenovirus-associated ARDS patients, 78.57% were men with a mean age of 54.93 ± 19.04 years, younger than that of the non-adenovirus associated ARDS patients. Adenovirus-associated ARDS patients had no specific clinical characteristics, but they presented with decrease in the number of CD3+CD4+ T cells and higher serum creatinine during the early stage. The viral load and the positivity rate in the lower respiratory tract were higher than that of the upper respiratory tract in the patients with adenovirus-associated ARDS. All patients required invasive mechanical ventilation treatment. The average time from shortness of breath to the application of invasive ventilation was 24 h. Ten patients (71.43%) complicated by acute kidney injury, while 13 patients (71.43%) in the non-adenovirus associated ARDS group (P = 0.045). Additionally, 85.71% of the 14 adenovirus-associated ARDS patients survived. No significant differences were detected between the two groups regarding duration of ventilation, length of ICU stay and mortality. CONCLUSION: Adenovirus infection is an important cause of virus-related ARDS. The positivity rate of adenovirus infection in lower respiratory tract secretions was higher than that in upper respiratory tract secretions in these patients. Age, lower CD3+CD4+ T cells, and high serum creatinine may be were associated with adenovirus induce ARDS in adults required mechanical ventilation. Early identification and intervention to prevent disease progression are essential for reducing the mortality rate in these patients.

The association between neutrophil-to-lymphocyte count ratio and mortality in septic patients: a retrospective analysis of the MIMIC-III database.

BACKGROUND: Neutrophil-to-lymphocyte count ratio (NLCR) has been shown as a feasible parameter associated with outcomes of tumor patients and an accessible predictor of bacteremia. However, only a handful of research shed the light on the association between NLCR and outcomes of septic patients. This study is aimed to evaluate the association between NLCR and all-cause mortality in a population of adult septic patients. METHODS: We extracted clinical data from Medical Information Mart for Intensive Care (MIMIC)-III V1.4, a free, large-scale, single-center database. NLCR was computed individually. Patients were categorized by quartiles of NLCR. The associations between NLCR quartiles and 28-day all-cause mortality in septic patients were assessed using Cox proportional hazards models and subgroup analyzes. To evaluate the accuracy of NLCR in predicting 28-day mortality of sepsis, receiver operator characteristic curves (ROC), areas under the curve (AUC), and the Youden's J Index were calculated. Other outcomes included 7-day all-cause mortality, mortality in the intensive care units (ICU), in-hospital mortality and length of ICU stay. RESULTS: A total of 3,043 eligible patients were included in the study, of which, 760, 759, 766 and 758 patients were fallen in the first quartile (≤5.89), the second quartile (>5.89, ≤10.69), the third quartile (>10.69, ≤20.25) and the fourth quartile (>20.25) of NLCR, respectively. The 7-day mortality (13.4%, 9.9%, 13.6% and 14.2%; P=0.064) showed no difference in the four quartiles. In multivariate analysis, after adjusting for confounding factors, the highest NLCR quartile (>20.25) was associated with increased 28-day all-cause mortality [hazard ratio (HR) 1.22, 95% Cl: 1.01-1.49; P=0.046]. The areas under the receiver operating characteristic curves (AUROCs) for NLCR was 0.553 (95% CI: 0.529-0.576) for 28-day mortality. CONCLUSIONS: High NLCR (>20.25) is independently related to increased 28-day all-cause mortality in adult septic patients of a limited sensibility and specificity. Further large multi-center prospective studies are needed to confirm such relationship and to validate whose clinical significance.

Classical swine fever virus C-strain with eight mutation sites shows enhanced cell adaptation and protects pigs from lethal challenge.

Control of classical swine fever (CSF) in developing countries is achieved by immunization with attenuated vaccines, such as the lapinized C-strain vaccine that has been widely used in China. However, C-strain has relatively low growth rate in cell cultures, thus affecting productivity of the vaccine for the industry. In this study, eight amino acid residues were mutated on the C-strain backbone, resulting in a cell-adapted strain Cmut8. The mutant strain exhibited rapid growth with titer of about 100 fold higher than its parental C-strain. The mutation sites located at structural proteins Erns and E2 contributed more to cell adaptation than those located in non-structural proteins. Sera collected from pigs inoculated with Cmut8 and C-strain at the same dose showed similar antibody levels and neutralization titers. Pigs inoculated with different doses of Cmut8 (low, medium and high) and with C-strain offered full protection against challenge with a virulent strain, shown as absence of fever and other symptoms, marginal low levels of viral load, and no obvious gross pathological changes in major organs. Unvaccinated control pigs challenged with the virulent strain showed high fever from day 2 post-challenge and apparent clinical symptoms with two deaths. Viral load were markedly elevated in these control pigs after challenge. The pigs inoculated with high dose of Cmut8 did not show fever or other typical CSF symptoms, and no apparent pathological changes were observed in major organs. Besides, the Cmut8 strain did not induce typical fever response in rabbits. These results demonstrate that the cell-adapted Cmut8 strain remains non-pathogenic to the weaned pigs, provides full protection and could be a good candidate vaccine strain for improved yield at lower cost.

Identification and Modulation of Microenvironment Is Crucial for Effective Mesenchymal Stromal Cell Therapy in Acute Lung Injury.

Rationale: There are controversial reports on applications of mesenchymal stromal cells (MSCs) in patients with acute respiratory distress syndrome (ARDS). Objectives: We hypothesized that lung microenvironment was the main determinant of beneficial versus detrimental effects of MSCs during ARDS. Methods: Lung proteome was profiled in three models of injury induced by acid instillation and/or mechanical ventilation in mice. Human gene of glutathione peroxidase-1 was delivered before MSC administration; or MSCs carrying human gene of IL-10 or hepatocyte growth factor were administered after lung injury. An inhibitory cocktail against IL-6, fibronectin, and oxidative stress was used in in vitro studies using human small airway epithelial cells and human MSCs after exposure to plasma of patients with ARDS. Measurements and Main Results: Distinct proteomic profiles were observed in three lung injury models. Administration of MSCs protected lung from ventilator-induced injury, whereas it worsened acid-primed lung injuries associated with fibrotic development in lung environment that had high levels of IL-6 and fibronectin along with low antioxidant capacity. Correction of microenvironment with glutathione peroxidase-1, or treatment with MSCs carrying human gene of IL-10 or hepatocyte growth factor after acid-primed injury, reversed the detrimental effects of native MSCs. Proteomic profiles obtained in the mouse models were also similarly observed in human ARDS. Treatment with the inhibitory cocktail in samples of patients with ARDS retained protective effects of MSCs in small airway epithelial cells. Conclusions: MSCs can be beneficial or detrimental depending on microenvironment at the time of administration. Identification of potential beneficiaries seems to be crucial to guide MSC therapy in ARDS.

Tsr Chemoreceptor Interacts With IL-8 Provoking E. coli Transmigration Across Human Lung Epithelial Cells.

Bacterial colonization of epithelial surfaces and subsequent transmigration across the mucosal barrier are essential for the development of infection. We hypothesized that the methyl-accepting proteins (MCPs), known as chemoreceptors expressed on Escherichia coli (E. coli) bacterial surface, play an important role in mediating bacterial transmigration. We demonstrated a direct interaction between human interleukin-8 (IL-8) and Tsr receptor, a major MCP chemoreceptor. Stimulation of human lung epithelial cell monolayer with IL-8 resulted in increased E. coli adhesion and transmigration of the native strain (RP437) and a strain expressing only Tsr (UU2373), as compared to a strain (UU2599) with Tsr truncation. The augmented E. coli adhesion and migration was associated with a higher expression of carcinoembryonic antigen-related cell adhesion molecule 6 and production of inflammatory cytokines/chemokines, and a lower expression of the tight junction protein claudin-1 and the plasma membrane protein caveolin-1 in lung epithelial cells. An increased E. coli colonization and pulmonary cytokine production induced by the RP437 and UU2373 strains was attenuated in mice challenged with the UU2599 strain. Our results suggest a critical role of the E. coli Tsr chemoreceptor in mediating bacterial colonization and transmigration across human lung epithelium during development of pulmonary infections.

[The application of fibrobronchoscopy in extubation for patients suffering from acute exacerbation of chronic obstructive pulmonary disease with low cough peak expiratory flow].

OBJECTIVE: To investigate the value of the application of fibrobronchoscopy in extubation for patients suffering from acute exacerbation of chronic obstructive pulmonary disease (AECOPD) with low cough peak expiratory flow (CPEF). METHODS: A single-center prospective controlled study was conducted. The ventilated AECOPD patients who were cooperative at the time of extubation in Department of Critical Care Medicine of Guangzhou Institute of Respiratory Disease of Guangzhou Medical University from June 2009 to May 2014 were enrolled. All patients successfully passed the spontaneous breathing trial (SBT). Extubation was performed after determination of CPEF following energetic coughing. According to the CPEF, the patients were divided into CPEF ≥ 60 L/min group (high CPEF group) and CPEF<60 L/min group (low CPEF group). After extubation, fibrobronchoscopic drainage was given to the patients in high CPEF group when necessary. Fibrobronchoscopic drainage was given to the patients in low CPEF group at least once a day, and the frequency of such treatment could be increased according to the patient's condition. If the patients did not require re-intubation within 48 hours,extubation was recorded as successful. The gender, age, acute physiology and chronic health evaluationII (APACHEII) score before extubation, ventilation time, the time of intensive care unit (ICU) stay, the mortality in ICU, the rate of re-intubation, the ability to cough and the frequency of application of fibrobronchoscopy after extubation were recorded. RESULTS: A total of 102 patients with AECOPD were enrolled, 58 patients in high CPEF group and 44 in low CPEF group. Compared with high CPEF group, the mean age in low CPEF group was older (years: 74.3 ± 15.2 vs. 69.5 ± 11.4, t=2.164, P=0.041), the time of ICU stay was significantly longer (days: 20.1 ± 11.2 vs. 17.4±7.3, t=2.274, P=0.030), but there was no significant difference in gender [male/female (cases):35/9 vs. 45/13, χ² = 0.057, P=0.812], APACHEII score (11.9 ± 1.9 vs. 10.3 ± 4.2, t=1.290, P=0.200), mechanical ventilation time (days: 14.8 ± 10.8 vs. 13.3 ± 9.6, t=0.677, P=0.501) and the rate of re-intubation [18.18% (8/44) vs. 12.07% (7/58), χ² = 1.412, P=0.235] between low CPEF group and high CPEF group. The cough strength of patients in high CPEF group was almost always "strong" (52 cases), and in the low CPEF group, most of them was "moderate" (14 cases) or "weak" (26 cases). The frequency of application of fibrobronchoscopy in low CPEF group was higher than that in high CPEF group (times: 4.1 ± 1.8 vs. 1.3 ± 0.9, t=2.626, P=0.011). All patients underwent weaning successfully, and no death occurred. CONCLUSIONS: The application of fibrobronchoscopy in the extubated AECOPD patients with low CPEF can reduce the rate of re-intubation, avoid the prolonged ventilation, but cannot reduce the time of ICU stay.

Vertebral osteomyelitis and epidural abscess due to Aspergillus nidulans resulting in spinal cord compression: case report and literature review.

Vertebral osteomyelitis caused by Aspergillus nidulans is rare and usually affects immunocompromised patients. This report presents a case of thoracic vertebral osteomyelitis with epidural abscesses due to A. nidulans in a 40-year-old immunocompetent female who presented with back pain, numbness and weakness of both lower limbs. Magnetic resonance imaging demonstrated osteomyelitis involving the thoracic (T)1-T3 vertebral bodies with epidural abscesses, resulting in spinal compression. The patient underwent a decompression laminectomy of T1-T3 and debridement of the thoracic epidural inflammatory granuloma. Histopathology revealed fungal granulomatous inflammation. The patient received 6 mg/kg voriconazole every 12 h (loading dose on day 1) followed by 4 mg/kg voriconazole twice daily for 1 month, administered intravenously. The patient returned with recurrent back pain 16 months after initial presentation. A. nidulans was identified by fungal culture and polymerase chain reaction. The patient showed no evidence of recurrence 1 year after a 6-month course of oral voriconazole. The key to the effective treatment of Aspergillus osteomyelitis is not to excise the abscess, but to administer systemic antifungal drug therapy.

Vasoactive intestinal peptide induces vascular endothelial growth factor production in human HaCaT keratinocytes via MAPK pathway.

Psoriasis is a chronic skin disease characterized by abnormal keratinocyte proliferation and differentiation, inflammation, and angiogenesis. Although dysfunction of the immune system is known to be an important factor in the pathogenesis of psoriasis, there is also strong evidence that psychological stresses are involved. Neuropeptides are thought to be main mediators of neurogenic inflammation, presumably involved in the pathogenesis of psoriasis. Vasoactive intestinal peptide (VIP) is one of the major neuropeptides in human and rodent skin. In the present study, we examined the effect and mechanism of VIP on vascular endothelial growth factor (VEGF) production by HaCaT cells which is a spontaneous, immortalized, human keratinocyte cell line. Our data indicate the mRNA and protein levels of VEGF by VIP were increased in a concentration-dependent manner. However, this increase was abrogated by pretreatment with an extracellular signal-regulated kinase (ERK) inhibitor PD98059 or p38MAPK inhibitor SB203580; pretreatment with c-Jun N-terminal kinase (JNK) inhibitor SP600125 did not attenuate the effects of VIP on the expression of VEGF. In addition, VIP treatment induced rapid phosphorylation of ERK1/2 and p38MAPK, and PD98059 and SB203580 were able to inhibit VIP-induced phosphorylation of ERK1/2 and p38MAPK, respectively. These results suggest that VIP increases the expression of VEGF through the ERK1/2 and p38MAPK signaling pathway in human HaCaT cells.

HSP70 and mucin 5B: novel protein targets of N,N'-dinitrosopiperazine-induced nasopharyngeal tumorigenesis.

N,N'-Dinitrosopiperazine (DNP) induces nasopharyngeal carcinoma (NPC) and shows organ specificity to the nasopharyngeal epithelium. To investigate its mechanism, the rat NPC model was induced using DNP. Rat NPC and normal nasopharyngeal cells were obtained from the NPC model using laser capture. The total proteins from these cell samples were separated with two-dimension polyacrylamide gel electrophoresis techniques, and highly expressed proteins (> five-fold) were analyzed using matrix-assisted laser desorption/ionization time of flight and bioinformatics. The results showed that HSP70 and mucin 5B expression increased not only in rat NPC but also in atypical hyperplasia nasopharyngeal tissues, a precancer stage of NPC. High-expression of heat shock protein 70 (HSP70) and mucin 5B was further supported by western blot analysis. The immunofluorescence and western-blotting studies further showed that DNP induced the expression of HSP70 and mucin 5B in a dosage-dependent manner in normal nasopharyngeal epithelia cells. Our data indicate that DNP triggers over-expression of HSP70 and mucin 5B, and is involved in nasopharyngeal tumorigenesis. HSP70 and mucin 5B may be important targets in nasopharyngeal tumorigenesis induced by DNP.