Ethnic disparities in cardiovascular and renal responses to canagliflozin between Asian and White patients with type 2 diabetes mellitus: A post hoc analysis of the CANVAS Program.

AIM: To assess the potential heterogeneity in cardiovascular (CV), renal and safety outcomes of canagliflozin between Whites and Asians, as well as these outcomes in each subgroup. MATERIALS AND METHODS: The CANVAS Program enrolled 10 142 patients with type 2 diabetes, comprising 78.34% Whites and 12.66% Asians. CV, renal and safety outcomes were comprehensively analysed using Cox regression models, while intermediate markers were assessed using time-varying mixed-effects models. Racial heterogeneity was evaluated by adding a treatment-race interacion term. RESULTS: Canagliflozin showed no significant racial disparities in the majority of the CV, renal and safety outcomes. The heterogeneity (p = .04) was observed on all-cause mortality, with reduced risk in Whites (hazard ratio 0.84; 95% confidence interval 0.71-0.99) and a statistically non-significant increased risk in Asians (hazard ratio 1.64; 95% confidence interval 0.94-2.90). There was a significant racial difference in acute kidney injury (p = .04) and a marginally significant racial heterogeneity for the composite of hospitalization for heart failure and CV death (p = .06) and serious renal-related adverse events (p = .07). CONCLUSION: Canagliflozin reduced CV and renal risks similarly in Whites and Asians; however, there was a significant racial discrepancy in all-cause mortality. This distinction may be attributed to the fact that Asian patients exhibited diminished CV protection effects and more renal adverse events with canagliflozin, potentially resulting from the smaller reductions in weight and uric acid. These findings highlight the importance of investigating the impact of race on treatment response to sodium-glucose cotransporter-2 inhibitors and provide more precise treatment strategies.

The correlation of serum long non-coding RNA ANRIL with risk factors, functional outcome, and prognosis in atrial fibrillation patients with ischemic stroke.

BACKGROUND: This study aimed to evaluate the predictive value of long non-coding RNA (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL) for atrial fibrillation (AF) patients with ischemic stroke and investigate its correlation with risk factors, functional outcome, and prognosis. METHODS: A total of 386 consecutive AF patients were recruited. AF patients were followed up for 24-48 months by outpatient follow-up, telephone follow-up, and medical record. The time of ischemic stroke in patients with AF was recorded, and follow-up was continued for 6 months. LncRNA ANRIL expression from serum was detected by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Compared with the AF with ischemic stroke group (14.3 ± 2.3), patients in the AF without ischemic stroke group (11.9 ± 1.8) had significantly lower serum lncRNA ANRIL levels (P < .05). The sensitivity and specificity of lncRNA ANRIL for identifying AF with ischemic stroke were 76.6% and 81.4%, respectively. Spearman correlation analysis results shown that lncRNA ANRIL was significantly correlated with the NIHSS score (rSpearman  = .490, P < .001) and the mRS score (rSpearman  = .466, P < .001). Compared with the lncRNA ANRIL high-expression group, the recurrence-free survival (RFS) of the lncRNA ANRIL low-expression group was significantly higher (χ2  = 11.009, log-rank P < .001). Cox proportional regression model analysis indicated that the serum lncRNA ANRIL level (P = .004), NIHSS score (P = .001), infarct volume (P = .035), and smoking (P < .001) were the risk factors for AF with ischemic stroke. CONCLUSION: Serum lncRNA ANRIL exerts a good predictive value for AF with ischemic stroke, and its increased expression is correlated with worse RFS for patients.

[Prognostic value of extra-vascular lung water index and pulmonary vascular permeability index in patients with ARDS].

OBJECTIVE: To investigate the correlation of the extra-vascular lung water index (EVLWI) and the pulmonary vascular permeability index (PVPI) with disease severity and their prognostic value in patients with acute respiratory distress syndrome (ARDS). METHODS: A total of 44 patients with ARDS from October 2012 to June 2014 admitted in the Second Affiliated Hospital of Wenzhou Medical University were recruited in this study. According to the severity, patients were divided into three groups (Mild group, Moderate group and Severe group); the acute physiology and chronic health evaluation system II score (APACHE II), the lung injury score (LIS), the pulse contour curve continuous cardiac output (PiCCO) and other clinical indicators were respectively monitored in the period of 24, 48, 72 hrs after admission; then the correlation of EVLWI, PVPI and oxygenation index (OI) among groups were analyzed; According to the prognosis, patients were divided into the survival group and the death group, both given the univariate and multivariate Logistic regression analysis; EVLWI, PVPI, APACHE II score, LIS and lactic acid were admitted into the receiver operating characteristic (ROC) curve analysis, and the prognosis was evaluated respectively. RESULTS: With the increase of disease severity, LIS and lactic acid gradually increased, the difference was significant among the three groups of Mild, Moderate and Severe (P<0.05). And the APACHE II score also increased gradually with the severity, but the difference was statistically significant only between the Mild group and the Severe group (P<0.01). And likewise, mild, moderate, severe ARDS patients had 1, 6, 9 cases of death, respectively. The 28-day mortality rate increased gradually after admission, with a significant difference between the Mild group and the Severe group (P<0.05). When all the 44 patients of three severities (during the 24 hrs period and during the 72 hrs period) were compared, the OI gradually decreased with the increase of severity of ARDS, while EVLWI and PVPI ascended, and differences between any two groups were statistically significant (P<0.05). In addition, there was a significant negative correlation between EVLWI and OI or between PVPI and OI (r=-0.666, -0.763, all P<0.01), and a significant positive correlation between EVLWI and PVPI, the APACHE II score or LIS (r=0.929, 0.895, 0.661, all P<0.01). Besides, OI was a predictive protection factor of ARDS, whereas lactic acid, EVLWI and PVPI were risk factors. Multivariate Logistic regression analysis showed that EVLWI and lactic acid were risk factors for ARDS death (all P<0.05). ROC curve analysis results suggested EVLWI and lactic acid were risk factors, (odd ratio (OR)> 1, and 95%CI: 1.071-5.201, 5.201-99.852, all P<0.05). CONCLUSION: EVLWI, PVPI were positively correlated with the severity of ARDS illness; EVLWI can be used as an independent risk factor for forecasting ARDS death, jointing EVLWI with PVPI could improve the accuracy of ARDS death forecasting.

[Regulatory effects of luteolin on airway inflammation in asthmatic rats].

OBJECTIVE: To explore the regulatory effects of luteolin on airway inflammation in asthmatic rats. METHODS: A total of 48 male Sprague-Dawley (SD) rats were randomly divided into 3 groups of control, asthmatic and luteolin(n = 16 each). The rat model of bronchial asthma was established in asthmatic and luteolin groups. The model was induced by intraperitoneally injecting a mixture of ovalbumin and aluminum hydroxide at Day 1 and 8. After two weeks, aomization excitation of normal saline (containing 1% ovalbumin) was induced thrice weekly. The treatment lasted 8 weeks. In control group, the mixture of ovalbumin, aluminum hydroxide and normal saline containing 1% ovalbumin was replaced by normal saline. At 30 min after aomization excitation, normal saline was given to rats in control and asthmatic groups, while 1 mg/kg luteolin was given intraperitoneally to luteolin group. The inflammatory cell number and level of interleukin-4 (IL-4) were measured in bronchoalveolar lavage fluid (BALF). The histopathological changes were observed under light microscope. The activities of peroxisome proliferator-activated receptors (PPARγ) and p38 mitogen-activated protein kinases (p38MAPK) in pulmonary tissues were detected by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The bronchial wall thickness of asthma group, along with smooth muscle thickness ((93.3 ± 7.4), (34.9 ± 2.3) µm) was more than that of control ((61.9 ± 8.2), (19.3 ± 1.5) µm) and luteolin ((76.6 ± 6.7), (25.4 ± 4.6) µm) groups (all P < 0.05). The total cell count ((5.61 ± 0.63)×10(9)/L), neutrophil count ((1.83 ± 0.09)×10(9)/L), eosinophil count ((0.59 ± 0.09)×10(9)/L) and level of IL-4 ((78.23 ± 12.73) pg/ml) in BALF of asthmatic group were markedly higher than those of control ((1.53 ± 0.31)×10(9)/L, (0.45 ± 0.21)×10(9)/L, (0.07 ± 0.03) ×10(9)/L and (21.21 ± 2.53) pg/ml) and luteolin ((3.24 ± 0.25)×10(9)/L, (1.54 ± 0.10)×10(9)/L, (0.33 ± 0.05)×10(9)/L and (43.24 ± 8.65) pg/ml) groups (all P < 0.05). The results of semi-quantitative immunohistochemical analysis showed that the p38 protein level in control group (0.143 ± 0.017) and luteolin group (0.251 ± 0.021) was significantly less than that in asthmatic group (0.362 ± 0.008) (both P < 0.01). As compared with asthmatic group, the expression of PPARγ protein markedly increased (0.247 ± 0.034) in control (0.331 ± 0.056) and luteolin (0.442 ± 0.031) groups (all P < 0.05). The level of p38 mRNA in asthmatic group (0.718 ± 0.064) was significantly higher than that of control (0.312 ± 0.052) and luteolin (0.426 ± 0.067) groups (all P < 0.01). However, the PPARγ mRNA level in asthmatic group (0.266 ± 0.036) was much less than that in control (0.573 ± 0.042) and luteolin (0.687 ± 0.054) groups (all P < 0.01). CONCLUSION: The anti-inflammatory effects of luteolin may be associated with the regulation of PPARγ expression and p38MAPK signaling pathway in asthmatic rats.

[Effects of catalpol, L-shikonin and paeonol extracted from radix rehmanniae, radix arnebiae and cortex moutan on KGF-induced HaCaT cell proliferation].

OBJECTIVE: To explore the effects of Chinese herbal medicine radix rehmanniae, radix arnebiae and cortex moutan on the proliferation of HaCaT cells and explore their potential curative mechanisms. METHODS: The main monomers of catalpol, l-shikonin and paeonol were extracted. And 10 ng/ml keratinocyte growth factor (KGF) was used to induce HaCaT cell to build an in vitro model of hyperproliferation of epidermal keratinocytes. CCK-8 assay and flow cytometry were applied to examine the effects of herbal monomers on cell proliferation and cell cycle. RESULTS: Both l-shikonin ( ≥ 10(-6) mol/L) and paeonol ( ≥ 1.88×10(-4) mol/L) inhibited cell proliferation while catalpol ( ≥ 10(-6) mol/L) enhanced cell proliferation.L-shikonin ( ≥ 10(-6) mol/L) and paeonol ( ≥ 1.88×10(-4) mol/L) inhibited the HaCaT cell during S and G2M phases while catalpol ( ≥ 10(-6) mol/L) enhanced HaCaT cell during S phase but not G2M phase. CONCLUSION: L-shikonin and paeonol inhibits the proliferation of HaCaT cells while catalpol has opposite effects.

[Functional role of caveolin-1 in airway smooth muscle cells proliferation and regulatory effect of roxithromycin].

OBJECTIVE: To explore the functional role of caveolin-1 in airway smooth muscle cells (ASMCs) proliferation and examine the regulatory effect of roxithromycin. METHODS: The rat model of bronchial asthma was established. Electron microscope was employed to observe the status of caveolae and light microscope for the histological changes in pulmonary tissues. The primarily cultured ASMCs were divided into 5 groups: control (group A), asthmatic ASMCs (group B), PD98059 (group C), roxithromycin (group D) and methyl-ß-cyclodextrin (group E). Cell proliferation was detected by Cell Counting Kit-8 (CCK-8). And the expressions of caveolin-1, extracellular regulated protein kinases (ERK) and monocyte chemotactic protein (MCP)-1 were detected by Western blot and reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The cell proliferation of asthmatic ASMCs (0.68 ± 0.15, 0.63 ± 0.13) in groups C and D were significantly less than those in group B (0.96 ± 0.14) (both P < 0.05) while group E was more than group B (1.26 ± 0.11 vs 0.96 ± 0.14, P < 0.05). The content of caveolin-1 (0.392 ± 0.064, 0.332 ± 0.057) in groups C and D were higher than those in group B (0.237 ± 0.032) (both P < 0.05) while ERK1/2 protein level in groups C and D (0.241 ± 0.017, 0.268 ± 0.007) were less than those in group B (0.346 ± 0.009) (both P < 0.01). And MCP-1 protein level in groups C and D (0.198 ± 0.015, 0.286 ± 0.019) were less than those in group B (0.482 ± 0.026) (both P < 0.01). The ERK mRNA level in groups C and D (0.277 ± 0.043, 0.338 ± 0.026) were less than those in group B (0.591 ± 0.022) (both P < 0.01). And also MCP-1 mRNA in groups C and D (0.212 ± 0.042, 0.249 ± 0.032) were less than those in group B (0.676 ± 0.053) (all P < 0.01) CONCLUSIONS: Caveolin-1 preventing the proliferation of asthmatic ASMCs is most likely mediated by ERK1/2 signal pathway and a down-regulation of MCP-1 expression. And roxithromycin reduces the proliferation of asthmatic ASMCs through up-regulating the expression of caveolin-1 and inhibiting the expression of MCP-1.

The toxicokinetic and extracorporeal removal of bongkrekic acid during blood purification therapies: A case report.

Bongkrekic acid (BA) poisoning can progress rapidly and lead to the failure of multiple organs, such as brain, liver and kidney. The mortality of BA poisoning is 40-100%. Little information is available on the toxicokinetic parameters of BA in human. Although hemodialysis is widely utilized for patients with severe BA poisoning, the exact amount of BA removed by hemodialysis is poorly documented. We analyzed toxicokinetic parameters, endogenous clearance and hemodialysis clearance in a patient with BA poisoning. A 27-year-old male developed symptoms of severe diarrhea, nausea, vomiting and weakness after eating rice noodles for more than one day. The patient developed multiple organ failures, especially the liver. Initial serum BA concentration was 0.5µg/mL. He received plasmapheresis, routing, and Oxiris-based Continuous Renal Replacement Therapy (CRRT). The whole blood, serum, urine and dialysate BA concentrations were collected and analyzed hourly. Toxicokinetic parameters relationships were determined using noncompartmental analysis. The clearances were determined using standard pharmacokinetic calculations. The disposition of BA was characterized by a long half-life (t1/2 of 102) and high max plasma (CL of 129,000 L/h/kg) following ingestion of contaminated food. The average serum clearance of BA during PE is remarkable higher than CRRT and the endogenous clearance. In contrast, the rates of decline in blood levels during the CRRT treatments were similar to the natural rate of decline. The total amount of BA removed by Plasmapheresis was 5.51mg. However, most CRRT failed to eliminate BA. We report a rare case of BA poisoning with a complication of liver failure and acute kidney damage. The patient expired, even with supportive care, plasmapheresis and hemodialysis. Analysis of whole blood, serum, urine and dialysate concentrations showed limited efficacy of CRRT in removing BA from blood. In contrast, there was significant extraction of BA from Plasmapheresis.

MiR-26a inhibits the inflammatory response of microglia by targeting HMGA2 in intracerebral hemorrhage.

OBJECTIVE: Intracerebral hemorrhage (ICH) is a common cerebrovascular disease with high mortality and poor prognosis. Therefore, the biological function and underlying molecular mechanism of miR-26a in inflammatory injury following ICH was investigated. METHODS: The potential role of miR-26a was investigated in lipopolysaccharide (LPS)-treated microglial cells by quantitative real-time PCR. To explore the potential role of HMGA2 in the miR-26a-regulated inflammatory response, LPS-induced microglial cells were cotransfected with an miR-26a mimic and pcDNA-HMGA2. Then, lentivirus-mediated overexpression of an miR-26a mimic in mouse microglial cells was performed, and the effects of miR-26a treatment on IL-6, IL-1ß, and TNF-α expression in the mouse brain, neurological behavior, and rotarod test performance of mice after ICH were observed. RESULTS: MiR-26a was significantly downregulated in LPS-treated microglia and ICH mouse models. MiR-26a markedly reduced IL-6, IL-1ß, and TNF-α expression in LPS-treated microglial cells. Furthermore, HMGA2 was verified as a direct target of miR-26a. In vivo, miR-26a overexpression in mouse microglial cells significantly suppressed proinflammatory cytokine expression in mouse brains and markedly improved the neurological behavior and rotarod test performance of mice after ICH. CONCLUSION: MiR-26a remarkably inhibited proinflammatory cytokine release by targeting HMGA2, indicating that miR-26a could protect against secondary brain injury following ICH.

Effects of tree species richness on fine root production varied with stand density and soil nutrients in subtropical forests.

Fine root production accounts for a large proportion of net primary production (NPP) in forest ecosystems that is highly responsive to environmental and biotic changes. The underlying mechanisms of the relationship between tree species richness and fine root production have not been fully examined. Here we hypothesized that: (i) the relationship between aboveground species richness and fine root production could be attributable to belowground spatial resource partitioning; (ii) either symmetrical or asymmetrical root proliferation to obtain nutrients leads to increased fine root production; and (iii) stand density affects the relationship between species richness and fine root production. We used an ingrowth core method to estimate fine root production coupled to molecular approaches for identifying the tree species of sampled fine roots within each ingrowth core. There was a significant and positive relationship between aboveground species richness and fine root production. The increase in fine root production might partially be attributed to asymmetrical root proliferation rather than belowground spatial resource partitioning. A piecewise structural equation model (SEM) linking stand density and soil nutrients revealed that both factors play dominant roles in mediating the effects of aboveground species richness on fine root production. Moreover, fine root production and relative abundance of fine root distribution within-layers both depended on the effects of aboveground species richness × stand density × soil phosphorus (P) interactions. Therefore, soil P concentration and stand density partially explained the positive aboveground species richness-fine root production relationship.

The function of KptA/Tpt1 gene - a minor review.

Rapid response of uni- and multicellular organisms to environmental changes and their own growth is achieved through a series of molecular mechanisms, often involving modification of macromolecules, including nucleic acids, proteins and lipids. The ADP-ribosylation process has ability to modify these different macromolecules in cells, and is closely related to the biological processes, such as DNA replication, transcription, signal transduction, cell division, stress, microbial aging and pathogenesis. In addition, tRNA plays an essential role in the regulation of gene expression, as effector molecules, no-load tRNA affects the overall gene expression level of cells under some nutritional stress. KptA/Tpt1 is an essential phosphotransferase in the process of pre-tRNA splicing, releasing mature tRNA and participating in ADP-ribose. The objective of this review is concluding the gene structure, the evolution history and the function of KptA/Tpt1 from prokaryote to eukaryote organisms. At the same time, the results of promoter elements analysis were also shown in the present study. Moreover, the problems in the function of KptA/Tpt1 that have not been clarified at the present time are summarised, and some suggestions to solve those problems are given. This review presents no only a summary of clear function of KptA/Tpt1 in the process of tRNA splicing and ADP-ribosylation of organisms, but also gives some proposals to clarify unclear problems of it in the future.

Prognostic value of circulating lymphocyte B and plasma immunoglobulin M on septic shock and sepsis: a systematic review and meta-analysis.

OBJECTIVE: Normal B lymphocyte function and antibody secretion during inflammation can provide critical protection for the host. We aimed to synthesize existing evidence to explore whether circulating B cells and plasma immunoglobulin M (IgM) levels were associated with survival during sepsis. METHODS: PubMed, Embase, ISI Web of Knowledge, Cochrane Central Register of Controlled Trials were systematically searched. Studies with data on circulating B cells and plasma IgM levels within the initial 24 hours after sepsis onset were selected. RESULTS: A total of 11 studies were qualified for inclusion in this systematic review and meta-analysis with a total of 829 patients with sepsis and/or septic shock. Number of circulating B cells was similar between septic patients and health controls (SMD = -1.81, 95% CI: -4.15, 0.54; P = 0.13, I2 = 99%), while it was significantly reduced in sepsis survivors versus sepsis non-survivors (SMD = -0.60, 95% CI: -0.87, -0.32; P < 0.0001, I2 = 0%). Concentration of plasma IgM level was significantly decreased in septic patients as compared with healthy controls. Also, the plasma IgM level was significantly lower in sepsis survivors versus sepsis non-survivors. CONCLUSIONS: A poor prognostic survival outcome was observed for patients with decreased circulating B cells as well as IgM levels within the initial 24 h after sepsis onset.

A molecular method to identify species of fine roots and to predict the proportion of a species in mixed samples in subtropical forests.

Understanding of belowground interactions among tree species and the fine root (≤2 mm in diameter) contribution of a species to forest ecosystem production are mostly restricted by experimental difficulties in the quantification of the species composition. The available approaches have various defects. By contrast, DNA-based methods can avoid these drawbacks. Quantitative real-time polymerase chain reaction (PCR) is an advanced molecular technology, but it is difficult to develop specific primer sets. The method of next-generation sequencing has several limitations, such as inaccurate sequencing of homopolymer regions, as well as being time-consuming, and requiring special knowledge for data analysis. This study evaluated the potential of the DNA-sequence-based method to identify tree species and to quantify the relative proportion of each species in mixed fine root samples. We discriminated the species by isolating DNA from individual fine roots and amplifying the plastid trnL(UAA; i.e., tRNA-Leu-UAA) intron using the PCR. To estimate relative proportions, we extracted DNA from fine root mixtures. After the plastid trnL(UAA) intron amplification and TA-cloning, we sequenced the positive clones from each mixture. Our results indicated that the plastid trnL(UAA) intron spacer successfully distinguished tree species of fine roots in subtropical forests. In addition, the DNA-sequence-based approach could reliably estimate the relative proportion of each species in mixed fine root samples. To our knowledge, this is the first time that the DNA-sequence-based method has been used to quantify tree species proportions in mixed fine root samples in Chinese subtropical forests. As the cost of DNA-sequencing declines and DNA-sequence-based methods improve, the molecular method will be more widely used to determine fine root species and abundance.