Dysfunctional high-density lipoprotein activates toll-like receptors via serum amyloid A in vascular smooth muscle cells.

Serum amyloid A (SAA) is an uremic toxin and acute phase protein. It accumulates under inflammatory conditions associated with high cardiovascular morbidity and mortality in patients with sepsis or end-stage renal disease (ESRD). SAA is an apolipoprotein of the high-density lipoprotein (HDL). SAA accumulation turns HDL from an anti-inflammatory to a pro-inflammatory particle. SAA activates monocyte chemoattractant protein-1 (MCP-1) in vascular smooth muscle cells. However, the SAA receptor-mediated signaling pathway in vascular cells is poorly understood. Therefore, the SAA-mediated signaling pathway for MCP-1 production was investigated in this study. The SAA-induced MCP-1 production is dependent on the activation of TLR2 and TLR4 as determined by studies with specific receptor antagonists and agonists or siRNA approach. Experiments were confirmed in tissues from TLR2 knockout, TLR4 deficient and TLR2 knock-out/TLR4 deficient mice. The intracellular signaling pathway is IκBα and subsequently NFκB dependent. The MCP-1 production induced by SAA-enriched HDL and HDL isolated from septic patients with high SAA content is also TLR2 and TLR4 dependent. Taken together, the TLR2 and TLR4 receptors are functional SAA receptors mediating MCP-1 release. Furthermore, the TLR2 and TLR4 are receptors for dysfunctional HDL. These results give a further inside in SAA as uremic toxin involved in uremia-related pro-inflammatory response in the vascular wall.

Resolution acute respiratory distress syndrome through reversing the imbalance of Treg/Th17 by targeting the cAMP signaling pathway.

Acute respiratory distress syndrome (ARDS) is a severe cause of respiratory failure with a mortality rate as high as 40­46% and without any effective pharmacological treatment available. The present study provided a novel strategy for the treatment of ARDS by specifically interfering with cyclic adenosine monophosphate (cAMP) signaling. Pre-treatment with the phosphodiesterase antagonist pentoxifyllinum (PTX) obviously attenuated lung injury and reduced the mortality of mice with cecal ligature and puncture (CLP)­induced ARDS, while raising cAMP levels. In addition, pre­treatment with PTX attenuated CLP­induced increases in the number of T­regulatory cells (Tregs) and interleukin (IL)­17­producing T­helper lymphocytes (Th17) among spleen lymphocytes, while partially restoring the Treg/Th17 ratio. Correspondingly, CLP­induced increases in the secretion of IL­2, IL­6, IL­10 and IL­17 were attenuated. Furthermore, CLP­induced increases in forkhead box p3 and RAR­related orphan receptor Î³t (RORγt) expression as well as signal transducer and activator of transcription (STAT3) activation were attenuated by PTX. The results indicated that PTX­induced increases in cAMP may have partly restored the Treg/Th17 balance by modulating the transcription of Foxp3 and RORγt through the STAT3 pathway. In conclusion, the present study provided a novel treatment strategy for ARDS by modulating the balance of Treg/Th17 and the subsequent immune response via cAMP signaling, which requires pre-clinical and clinical validation.

Association of the Number of Years Since Menopause with Metabolic Syndrome and Insulin Resistance in Chinese Urban Women.

BACKGROUND: This study aimed to assess the prevalence of metabolic syndrome (MetS) and the association of years since menopause with MetS and Insulin Resistance (IR) in Chinese women. METHOD: A total of 4436 Chinese subjects aged 40-80 years participated in the study; 790 were premenopausal women, and 3646 were postmenopausal women. IR was arbitrarily defined as a homeostasis model assessment-IR index (HOMA-IR) value above the 75th percentile of normal glucose tolerance (NGT). MetS was defined according to the International Diabetes Federation consensus definition. To test whether there was an association between the number of years since menopause and MetS, multivariate logistic analysis was conducted. Premenopausal women were used as a comparison group in regression analyses. RESULTS: After adjustment for age, body mass index (BMI), and γ-glutamyltransferase (GGT), more years since menopause was highly associated with an increased risk of MetS (p for trend <0.05) ; the number of years since menopause was not correlated with fasting insulin and HOMA-IR. Postmenopausal women with 10 to 14 years since menopause had the highest risk (odds ratio [OR], 2.10; 95% confidence interval [CI], 1.52-2.89, p < .05) of MetS, high triglycerides (TG; OR, 1.80; 95% CI, 1.34-2.42, p < .05) and high glucose (OR, 1.52; 95% CI, 1.14-2.05, p < .05) and low high-density lipoprotein cholesterol (HDL-C; OR, 1.38; 95% CI, 1.18-2.32, p < .05). Postmenopausal women with more than 15 years since menopause had the highest risk of abdominal obesity (OR, 1.69; 95% CI, 1.05-2.71, p < .05). CONCLUSION: In China, more years since menopause was highly associated with an increased risk of MetS. Menopausal history may help identify women with increased risk of developing MetS.

Dectin-2 polymorphism associated with pulmonary cryptococcosis in HIV-uninfected Chinese patients.

Dectin-2 is a C-type lectin receptor that can recognize critical structures of fungi and involve in the host immune response after pulmonary fungal infections. We aimed to investigate the association between Dectin-2 genetic polymorphisms and cryptococcosis among a series of human immunodeficiency virus (HIV)-uninfected Chinese patients. In this case control study, a total of 251 patients with cryptococcosis and 464 healthy controls were included. One tag-single nucleotide polymorphism (SNP) (rs11045418) located at 5'-flanking region of Dectin-2 gene was selected and genotyped in this study. Among 251 patients, there were 108 (43%) meningitis patients including 73 (67.7%) healthy ones, 74 (29.5%) pulmonary infected patients including 49 (66.2%) healthy ones, and 69 (27.5%) patients with both neural and pulmonary infection including 38 (55.1%) immunocompetent ones. One hundred and forty-three (74 plus 69) patients with pulmonary cryptococcosis and 177 (108 plus 69) patients with cryptococcal meningitis were compared with controls, respectively. Three samples from 143 pulmonary infected patients failed in genotyping. There was a significant difference between 86 immunocompetent pulmonary infected patients and controls in the overdominant model (C/T vs. T/T + C/C; OR, 0.59; 95%CI, 0.37-0.94; P, .026). Similar but not significant difference was found between the overall pulmonary infected patients and the controls in the overdominant model (OR, 0.77; 95%CI, 0.52-1.12; P, .17). No such difference was found between controls and patients with cryptococcal meningitis. Our study firstly showed a genetic association between Dectin-2 and pulmonary cryptococcosis.

Early initiation of continuous renal replacement therapy improves clinical outcomes in patients with acute respiratory distress syndrome.

BACKGROUND: The acute respiratory distress syndrome (ARDS) is a common devastating syndrome in intensive care unit in critically ill patients. Continuous renal replacement therapy (CRRT) has been shown beneficial effects on oxygenation and survival in patients with ARDS. However, it is still controversial about the timing of initiation of CRRT. METHODS: Fifty-three patients with ARDS admitted to intensive care unit in Zhejiang Provincial People's Hospital, China from 2009 to 2013 were enrolled in the study. The authors compared ventilation parameter, including PaO2/FIO2, A-a gradient, positive end-expiratory pressure, plateau pressure, dynamic compliance and hemodynamic parameters, including central venous pressure, mean arterial pressure, cardiac index, extravascular lung water index, fluid balance between early initiation (within 12 hours after ARDS onset) and late initiation of CRRT (48 hours after ARDS onset) groups. The authors further investigated transforming growth factor (TGF)-ß1 level changes in serum and bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assay during 7 days of follow-up. RESULTS: Significant improvement of oxygenation and shorter duration of mechanical ventilation were observed in early CRRT group during 7-day follow-up. In addition, TGF-ß1 concentrations in serum and BALF were significantly decreased in patients with early initiation of CRRT compared to those with late initiation of CRRT on day 2 and day 7. Furthermore, patients who died of ARDS had higher levels of TGF-ß1 in BALF than survivors. CONCLUSIONS: Our findings showed that early initiation of CRRT is associated with favorable clinical outcomes in ARDS patients, which might be due to the reduced serum and BALF TGF-ß1 levels through CRRT. However, large multi-center studies are needed to make further recommendations as to the optimal use of CRRT in ARDS patient populations.

Urinary netrin-1 and KIM-1 as early biomarkers for septic acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) during sepsis is associated with poor outcome. However, diagnosis of AKI with serum creatinine (SCr) level change is neither highly sensitive nor specific. Therefore, identification of novel biomarkers for early diagnosis of AKI is desirable. AIMS: To evaluate the capacity of combining urinary netrin-1 and human kidney injury molecule type 1 (KIM-1) in the early diagnosis of septic AKI. METHODS: We prospectively recruited 150 septic patients from Jun 2011 to Jun 2013 at Zhejiang Provincial People's Hospital, China. SCr, urinary netrin-1, and KIM-1 levels were recorded at 0, 1, 3, 6, 24, and 48 h of ICU admission and compared between AKI and non-AKI patients. In addition, we investigated the prognostic value of netrin-1 and KIM-1 between non-survivors and survivors in septic AKI patients. RESULTS: SCr levels started to show elevation after 24 h of ICU admission. However, netrin-1 levels increased significantly as early as 1 h, peaked at 3-6 h and remained elevated up to 48 h of ICU admission in septic AKI patients. KIM-1 increased significantly by 6 h, peaked at 24 h and remained significantly elevated until 48 h of ICU admission. Furthermore, we observed significant higher urinary KIM-1 levels at 24 h and 48 h in non-survivors compared to survivors in AKI patients. CONCLUSIONS: Our results suggest that both netrin-1 and KIM-1 are clinically useful as early biomarkers in the diagnosis of septic AKI. In addition, persistent elevation of urinary KIM-1 level may be associated with poor prognosis.

Association of Fcγ receptor IIB polymorphism with cryptococcal meningitis in HIV-uninfected Chinese patients.

BACKGROUND: As important regulators of the immune system, the human Fcγ receptors (FcγRs) have been demonstrated to play important roles in the pathogenesis of various infectious diseases. The aim of the present study was to identify the association between FCGR polymorphisms and cryptococcal meningitis. METHODOLOGY/PRINCIPAL FINDINGS: In this case control genetic association study, we genotyped four functional polymorphisms in low-affinity FcγRs, including FCGR2A 131H/R, FCGR3A 158F/V, FCGR3B NA1/NA2, and FCGR2B 232I/T, in 117 patients with cryptococcal meningitis and 190 healthy controls by multiplex SNaPshot technology. Among the 117 patients with cryptococcal meningitis, 59 had predisposing factors. In patients with cryptococcal meningitis, the FCGR2B 232I/I genotype was over-presented (OR = 1.652, 95% CI [1.02-2.67]; P = 0.039) and the FCGR2B 232I/T genotype was under-presented (OR = 0.542, 95% CI [0.33-0.90]; P = 0.016) in comparison with control group. In cryptococcal meningitis patients without predisposing factors, FCGR2B 232I/I genotype was also more frequently detected (OR = 1.958, 95% CI [1.05-3.66]; P = 0.033), and the FCGR2B 232I/T genotype was also less frequently detected (OR = 0.467, 95% CI [0.24-0.91]; P = 0.023) than in controls. No significant difference was found among FCGR2A 131H/R, FCGR3A 158F/V, and FCGR3B NA1/NA2 genotype frequencies between patients and controls. CONCLUSION/SIGNIFICANCE: We found for the first time associations between cryptococcal meningitis and FCGR2B 232I/T genotypes, which suggested that FcγRIIB might play an important role in the central nervous system infection by Cryptococcus in HIV-uninfected individuals.

Genotypes coding for mannose-binding lectin deficiency correlated with cryptococcal meningitis in HIV-uninfected Chinese patients.

BACKGROUND: There is increasing evidence that mannose-binding lectin (MBL) has a complex role in many diseases, particularly in infectious diseases. However, the relationship between MBL deficiency and cryptococcal meningitis has not been clarified. The purpose of this study was to investigate the correlation between MBL polymorphism and non-HIV cryptococcal meningitis. METHODS: A case-controlled genetic association study was conducted. Patients with cryptococcal meningitis and control subjects were genotyped for 6 alleles of MBL2 gene (H/L, Y/X, P/Q, A/D, A/B, and A/C). The distributions in allele frequency, genotypes, haplotypes, and genotype groups were compared between patients and control subjects. RESULTS: Study participants included 103 HIV-uninfected patients with cryptococcal meningitis and 208 healthy control subjects, all of Chinese Han ethnicity. The homozygous mutative genotypes (O/O) of the coding region were associated with cryptococcal meningitis (P = .023; odds ratio [OR], 4.29; 95% confidence interval [CI], 1.11-19.88), the correlation more overt in immunocompetent patients (P = .005; OR, 6.65; 95% CI, 1.49-33.05). MBL-deficient participant group was associated with cryptococcal meningitis (P = .039; OR, 2.09; 95% CI, .96-4.51), particularly in immunocompetent patients (P = .028; OR, 2.51; 95% CI, .96-6.22). CONCLUSIONS: This is the first to show genotypes coding for MBL deficiency are associated with cryptococcal meningitis in nonimmunocompromised hosts.

Epidemiology and risk factors for non-Candida albicans candidemia in non-neutropenic patients at a Chinese teaching hospital.

The purpose of this study was to describe the epidemiology of nosocomial candidemia and identify risk factors involved in infections caused by non-C. albicans Candida species in a Chinese tertiary care center over a 10-year period. A total of 102 cases of nosocomial candidemia in non-neutropenic patients admitted from 1998 through 2007 were included in the study. Candida albicans remained the most common causative agent, accounting for 57.8% of all cases, followed by C. tropicalis (12.8%), C. parapsilosis (10.8%) and C. glabrata (10.8%). Comparison of C. albicans and non-C. albicans candidemia by multivariate logistic regression showed that factors independently associated with non-C. albicans candidemia included head trauma (OR, 5.34; 95% CI, 1.18-24.17; P = 0.029) and bacterial sepsis (OR, 3.58; 95% CI, 1.17-10.98; P = 0.026). Factors independently associated with C. albicans candidemia included tracheal intubation (OR, 0.26; 95% CI, 0.08-0.92; P = 0.037), and increased peripheral WBC count (OR, 0.84; 95% CI, 0.74-0.95; P = 0.006).