Neutrophil gelatinase-associated lipocalin, cystatin C and matrix metalloproteinase-9 as possible biomarkers in early detection of acute kidney injury after cardiac surgery

Introduction: Acute Kidney Injury (AKI) often occurs after open heart surgery. Today, serum creatinine is used as an indicator for identifying AKI; however, creatinine is unreliable due to delay in its elevation. Therefore, more reliable markers are required for early diagnosis of AKI. Aim: To measure the changes in Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Cystatin C (Cys C) levels and Matrix Metallo Proteinase 9 (MMP-9) activity in serum of patients who underwent cardiac surgery. Materials and Methods: The present descriptive study was conducted from September to October 2015 among patients referred to Cardiovascular Surgery Center at Shahid Modarres Hospital in Tehran, Iran. Urine and serum sample from 29 candidates for cardiac surgery were collected at 6 and 12 hours after surgery. On the basis of increase in serum creatinine, the patients were divided into two groups; AKI and control group. AKI group had at least 50 increase in serum creatinine; those with less than 50 increase were considered as control group. Urine NGAL and Cys C concentrations were measured using ELISA; MMP-9 activity was determined using gel zymography. Results: The results showed an increase in Cys C concentration in AKI group compared to control group after 6 and 12 hours of surgery. The comparison of Cys C concentration in AKI group between 6 and 12 hours after surgery showed no significant difference. The comparison of NGAL at 12 hours after surgery between control and AKI groups showed no significant difference. The MMP-9 activity showed a decreasing trend in AKI group compared to control group at 12 hours after surgery. Decrease in MMP-9 activity in AKI group at 6 hours after surgery was statistically different from after 12 hours of surgery. Conclusion: Present results provide evidence that Cys C and MMP-9 can be better reliable markers for early detection of AKI as compared to serum creatinine, after cardiac surgery. NGAL did not show higher sensitivity compared to creatinine in these patients. Therefore, Cys C and MMP-9 can be suggested as biomarkers for early detection of AKI after cardiac surgery. © 2018, Journal of Clinical and Diagnostic Research. All rights reserved

Neutrophil gelatinase-associated lipocalin, cystatin C and matrix metalloproteinase-9 as possible biomarkers in early detection of acute kidney injury after cardiac surgery

Introduction: Acute Kidney Injury (AKI) often occurs after open heart surgery. Today, serum creatinine is used as an indicator for identifying AKI; however, creatinine is unreliable due to delay in its elevation. Therefore, more reliable markers are required for early diagnosis of AKI. Aim: To measure the changes in Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Cystatin C (Cys C) levels and Matrix Metallo Proteinase 9 (MMP-9) activity in serum of patients who underwent cardiac surgery. Materials and Methods: The present descriptive study was conducted from September to October 2015 among patients referred to Cardiovascular Surgery Center at Shahid Modarres Hospital in Tehran, Iran. Urine and serum sample from 29 candidates for cardiac surgery were collected at 6 and 12 hours after surgery. On the basis of increase in serum creatinine, the patients were divided into two groups; AKI and control group. AKI group had at least 50 increase in serum creatinine; those with less than 50 increase were considered as control group. Urine NGAL and Cys C concentrations were measured using ELISA; MMP-9 activity was determined using gel zymography. Results: The results showed an increase in Cys C concentration in AKI group compared to control group after 6 and 12 hours of surgery. The comparison of Cys C concentration in AKI group between 6 and 12 hours after surgery showed no significant difference. The comparison of NGAL at 12 hours after surgery between control and AKI groups showed no significant difference. The MMP-9 activity showed a decreasing trend in AKI group compared to control group at 12 hours after surgery. Decrease in MMP-9 activity in AKI group at 6 hours after surgery was statistically different from after 12 hours of surgery. Conclusion: Present results provide evidence that Cys C and MMP-9 can be better reliable markers for early detection of AKI as compared to serum creatinine, after cardiac surgery. NGAL did not show higher sensitivity compared to creatinine in these patients. Therefore, Cys C and MMP-9 can be suggested as biomarkers for early detection of AKI after cardiac surgery. © 2018, Journal of Clinical and Diagnostic Research. All rights reserved

The transcription factor Zeb2 regulates development of conventional and plasmacytoid DCs by repressing Id2

Plasmacytoid dendritic cells (DCs [pDCs]) develop from pre-pDCs, whereas two lineages of conventional DCs (cDCs; cDC1s and cDC2s) develop from lineage-committed pre-cDCs. Several transcription factors (TFs) have been implicated in regulating the development of pDCs (E2-2 and Id2) and cDC1s (Irf8, Id2, and Batf3); however, those required for the early commitment of pre-cDCs toward the cDC2 lineage are unknown. Here, we identify the TF zinc finger E box-binding homeobox 2 (Zeb2) to play a crucial role in regulating DC development. Zeb2 was expressed from the pre-pDC and pre-cDC stage onward and highly expressed in mature pDCs and cDC2s. Mice conditionally lacking Zeb2 in CD11c(+) cells had a cell-intrinsic reduction in pDCs and cDC2s, coupled with an increase in cDC1s. Conversely, mice in which CD11c(+) cells overexpressed Zeb2 displayed a reduction in cDC1s. This was accompanied by altered expression of Id2, which was up-regulated in cDC2s and pDCs from conditional knock-out mice. Zeb2 chromatin immunoprecipitation analysis revealed Id2 to be a direct target of Zeb2. Thus, we conclude that Zeb2 regulates commitment to both the cDC2 and pDC lineages through repression of Id2

Terminal NK cell maturation is controlled by concerted actions of T-bet and Zeb2 and is essential for melanoma rejection

Natural killer (NK) cell maturation is a tightly controlled process that endows NK cells with functional competence and the capacity to recognize target cells. Here, we found that the transcription factor (TF) Zeb2 was the most highly induced TF during NK cell maturation. Zeb2 is known to control epithelial to mesenchymal transition, but its role in immune cells is mostly undefined. Targeted deletion of Zeb2 resulted in impaired NK cell maturation, survival, and exit from the bone marrow. NK cell function was preserved, but mice lacking Zeb2 in NK cells were more susceptible to B16 melanoma lung metastases. Reciprocally, ectopic expression of Zeb2 resulted in a higher frequency of mature NK cells in all organs. Moreover, the immature phenotype of Zeb2(-/-) NK cells closely resembled that of Tbx21(-/-) NK cells. This was caused by both a dependence of Zeb2 expression on T-bet and a probable cooperation of these factors in gene regulation. Transgenic expression of Zeb2 in Tbx21(-/-) NK cells partially restored a normal maturation, establishing that timely induction of Zeb2 by T-bet is an essential event during NK cell differentiation. Finally, this novel transcriptional cascade could also operate in human as T-bet and Zeb2 are similarly regulated in mouse and human NK cells

Aging diminishes the resistance of AO rats to EAE: putative role of enhanced generation of GM-CSF Expressing CD4+T cells in aged rats

Background: Aging influences immune response and susceptibility to EAE in a strain specific manner. The study was designed to examine influence of aging on EAE induction in Albino Oxford (AO) rats. Results: Differently from 3-month-old (young) rats, which were resistant to EAE induction, the majority of aged (24-26-month-old) rats developed mild chronic form of EAE. On 16th day post-immunization, when in aged rats the neurological deficit reached plateau, more mononuclear cells, including CD4+ T lymphocytes was retrieved from spinal cord of aged than young rats. The frequencies of IL-17+ and GM-CSF+ cells within spinal cord infiltrating CD4+ lymphocytes were greater in aged rats. To their increased frequency contributed the expansion of GM-CSF + IL-17 + IFN-gamma+ cells, which are highly pathogenic in mice. The expression of the cytokines (IL-1 beta and IL-23/p19) driving GM-CSF + IL-17 + IFN-gamma + cell differentiation in mice was also augmented in aged rat spinal cord mononuclear cells. Additionally, in aged rat spinal cord the expansion of GM-CSF + IL-17-IFN-gamma- CD4+ T lymphocytes was found. Consistently, the expression of mRNAs for IL-3, the cytokine exhibiting the same expression pattern as GM-CSF, and IL-7, the cytokine driving differentiation of GM-CSF + IL-17-IFN-gamma- CD4 + lymphocytes in mice, was upregulated in aged rat spinal cord mononuclear cells, and the tissue, respectively. This was in accordance with the enhanced generation of the brain antigen-specific GM-CSF+ CD4+ lymphocytes in aged rat draining lymph nodes, as suggested by (i) the higher frequency of GM-CSF+ cells (reflecting the expansion of IL-17-IFN-gamma- cells) within their CD4+ lymphocytes and (ii) the upregulated GM-CSF and IL-3 mRNA expression in fresh CD4+ lymphocytes and MBP-stimulated draining lymph node cells and IL-7 mRNA in lymph node tissue from aged rats. In agreement with the upregulated GM-CSF expression in aged rats, strikingly more CD11b + CD45(int) (activated microglia) and CD45(hi) (mainly proinflammatory dendritic cells and macrophages) cells was retrieved from aged than young rat spinal cord. Besides, expression of mRNA for SOCS1, a negative regulator of proinflammatory cytokine expression in innate immunity cells, was downregulated in aged rat spinal cord mononuclear cells. Conclusions: The study revealed that aging may overcome genetic resistance to EAE, and indicated the cellular and molecular mechanisms contributing to this phenomenon in AO rats

Developing criteria for Cesarean Section using the RAND appropriateness method

<p>Abstract</p> <p>Background</p> <p>Cesarean section rates are increasing worldwide, and a rapid increase has been observed in Iran. Disagreement exists between clinicians about when to use cesarean section. We aimed to identify the appropriateness criteria for the use of cesarean section in Iran.</p> <p>Method</p> <p>A consensus development study using a modified version of the RAND Appropriateness Method (RAM). We generated scenarios from valid clinical guidelines and expert opinions. A panel of experts participated in consensus development: first round via mail (12 members), second round face-to-face (9 members). We followed the RAM recommendations for the development of the scenario lists, rating scales, and statistical analyses.</p> <p>Results</p> <p>294 scenarios relevant to cesarean section were identified. 191 scenarios were considered appropriate, of which 125 scenarios were agreed upon. The panel found cesarean inappropriate for 21% of scenarios, and 'equivocal' for 14% of scenarios.</p> <p>Conclusion</p> <p>RAM is useful for identifying stakeholder views in settings with limited resources. The participants' views on appropriateness of certain indications differed with available evidence. A large number of scenarios without agreement may partly explain why it has been difficult to curb the growth in cesarean section rate.</p

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies