Urinary Biomarkers TIMP-2 and IGFBP7 Early Predict Acute Kidney Injury after Major Surgery

Objective

To assess the ability of the urinary biomarkers IGFBP7 (insulin-like growth factor-binding protein 7) and TIMP-2 (tissue inhibitor of metalloproteinase 2) to early predict acute kidney injury (AKI) in high-risk surgical patients.

Introduction

Postoperative AKI is associated with an increase in short and long-term mortality. Using IGFBP7 and TIMP-2 for early detection of cellular kidney injury, thus allowing the early initiation of renal protection measures, may represent a new concept of evaluating renal function.

Methods

In this prospective study, urinary [TIMP-2]×[IGFBP7] was measured in surgical patients at high risk for AKI. A predefined cut-off value of [TIMP-2]×[IGFBP7] >0.3 was used for assessing diagnostic accuracy. Perioperative characteristics were evaluated, and ROC analyses as well as logistic regression models of risk assessment were calculated with and without a [TIMP-2]×[IGFBP7] test.

Results

107 patients were included in the study, of whom 45 (42%) developed AKI. The highest median values of biomarker were detected in septic, transplant and patients after hepatic surgery (1.24 vs 0.45 vs 0.47 ng/l²/1000). The area under receiving operating characteristic curve (AUC) for the risk of any AKI was 0.85, for early use of RRT 0.83 and for 28-day mortality 0.77. In a multivariable model with established perioperative risk factors, the [TIMP-2]×[IGFBP7] test was the strongest predictor of AKI and significantly improved the risk assessment (p<0.001).

Conclusions

Urinary [TIMP-2]×[IGFBP7] test sufficiently detect patients with risk of AKI after major non-cardiac surgery. Due to its rapid responsiveness it extends the time frame for intervention to prevent development of AKI.     

Will urinary biomarkers provide a breakthrough in diagnosing cardiac surgery-associated AKI? – A systematic review

Abstract

Introduction: Acute kidney injury following cardiac surgery is a dreaded complication contributing to early mortality. Diagnosing AKI using serum creatinine usually results in a delay. To combat this, certain kidney damage specific biomarkers were investigated to identify if they can serve as early predictors of cardiac surgery-associated AKI (CSA-AKI). This study systematically reviews three such biomarkers; NGAL, tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP7) to identify if they can serve as early predictors of CSA-AKI.

Methods: Systematic search was carried out on literature reporting the diagnostic ability of the three biomarkers from databases in accordance with PRISMA guidelines.

Results: We found 43 articles reporting urinary-NGAL levels (n?=?34 in adults, n?=?9 in children) and 10 studies reporting TIMP-2 and IGFBP7 levels among adults. Interestingly, NGAL showed high diagnostic value in predicting AKI in children (seven among nine studies with AUROC?>?0.8). The cell cycle arrest biomarkers, namely TIMP-2 and IGFBP7, showed high diagnostic value in predicting AKI in adults (five among ten studies with AUROC?>?0.8).

Conclusion: In predicting CSA-AKI; the diagnostic value of NGAL is high in the paediatric population while the diagnostic value of TIMP-2 and IGFBP7 is high in adults.     

Urinary Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) ? Insulin-Like Growth Factor-Binding Protein 7 (IGFBP7) Predicts Adverse Outcome in Pediatric Acute Kidney Injury

Background

The G1 cell cycle inhibitors tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been identified as promising biomarkers for the prediction of adverse outcomes including renal replacement therapy (RRT) and mortality in critically ill adult patients who develop acute kidney injury (AKI). However, the prognostic value of urinary TIMP-2 and IGFBP7 in neonatal and pediatric AKI for adverse outcome has not been investigated yet.

Methods

The product of the urinary concentration of TIMP-2 and IGFBP7 ([TIMP-2]•[IGFBP7]) was assessed by a commercially available immunoassay (NephroCheck^™) in a prospective cohort study in 133 subjects aged 0–18 years including 46 patients with established AKI according to pRIFLE criteria, 27 patients without AKI (non-AKI group I) and 60 apparently healthy neonates and children (non-AKI group II). AKI etiologies were: dehydration/hypovolemia (n = 7), hemodynamic instability (n = 7), perinatal asphyxia (n = 9), septic shock (n = 7), typical hemolytic-uremic syndrome (HUS; n = 5), interstitial nephritis (n = 5), vasculitis (n = 4), nephrotoxic injury (n = 1) and renal vein thrombosis (n = 1).

Results

When AKI patients were classified into pRIFLE criteria, 6/46 (13%) patients fulfilled the criteria for the category “Risk”, 13/46 (28%) for “Injury”, 26/46 (57%) for “Failure” and 1/46 (2%) for “Loss”. Patients in the “Failure” stage had a median 3.7-fold higher urinary [TIMP-2]•[IGFBP7] compared to non-AKI subjects (P<0.001). When analyzed for AKI etiology, highest [TIMP-2]•[IGFBP7] values were found in patients with septic shock (P<0.001 vs. non-AKI I+II). Receiver operating characteristic (ROC) curve analyses in the AKI group revealed good performance of [TIMP-2]•[IGFBP7] in predicting 30-day (area under the curve (AUC) 0.79; 95% CI, 0.61–0.97) and 3-month mortality (AUC 0.84; 95% CI, 0.67–0.99) and moderate performance in predicting RRT (AUC 0.67; 95% CI, 0.50–0.84).

Conclusions

This study shows that urinary [TIMP-2]•[IGFBP7] has a good diagnostic performance in predicting adverse outcomes in neonatal and pediatric AKI of heterogeneous etiology.     

Validation of Cell-Cycle Arrest Biomarkers for Acute Kidney Injury after Pediatric Cardiac Surgery

Background

The lack of early biomarkers for acute kidney injury (AKI) seriously inhibits the initiation of preventive and therapeutic measures for this syndrome in a timely manner. We tested the hypothesis that insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, function as early biomarkers for AKI after congenital heart surgery with cardiopulmonary bypass (CPB).

Methods

We prospectively studied 51 children undergoing cardiac surgery with CPB. Serial urine samples were analyzed for [TIMP-2]•[IGFBP7]. The primary outcome measure was AKI defined by the pRIFLE criteria within 72 hours after surgery.

Results

12 children (24%) developed AKI within 1.67 (SE 0.3) days after surgery. Children who developed AKI after cardiac surgery had a significant higher urinary [TIMP-2]•[IGFBP7] as early as 4 h after the procedure, compared to children who did not develop AKI (mean of 1.93 ((ng/ml)²/1000) (SE 0.4) vs 0.47 ((ng/ml)²/1000) (SE 0.1), respectively; p<0.05). Urinary [TIMP-2]•[IGFBP7] 4 hours following surgery demonstrated an area under the receiver-operating characteristic curve of 0.85. Sensitivity was 0.83, and specificity was 0.77 for a cutoff value of 0.70 ((ng/ml)²/1000).

Conclusions

Urinary [TIMP-2]•[IGFBP7] represent sensitive, specific, and highly predictive early biomarkers for AKI after surgery for congenital heart disease.

Trial Registration

www.germanctr.de/, DRKS00005062     

Urinary cell cycle arrest biomarker [TIMP-2]·[IGFBP7] in patients with hepatorenal syndrome

Abstract

Background: Patients with hepatorenal syndrome carry a high short-term mortality. Early diagnosis and treatment are essential for patients’ outcome. Nevertheless diagnosis of HRS remains difficult. First-line therapy terlipressin is often associated with severe complications. Biomarkers become more on focus for an early diagnosis.

Objective: The aim of this study was to test the diagnostic accuracy of urinary [TIMP-2]·[IGFBP7] for HRS patients and prognostic value for therapy responding patients.

Material and methods: NephroCheck^® measures urinary concentrations of TIMP-2 and IGFBP-7, both indicating stress of renal cells and associated with induction of cell cycle arrest. 22 HRS patients and 30 patients with normal kidney function were included. [TIMP-2]·[IGFBP7] was measured using NephroCheck^®. HRS patients receiving terlipressin were also examined.

Results: [TIMP-2]·[IGFBP7] values did not differ significantly (1.3?±?2.09 vs. 1.03?±?1.03; p?=?0.55). Furthermore, there was no significant difference of [TIMP-2]·[IGFBP7] regarding response of terlipressin (1.32?±?2.39 vs. 0.81?±?1.05; p?=?0.56). Low [TIMP-2]·[IGFBP7] values were significantly associated with higher mortality (p?=?0.01).

Conclusions: The results of this study suggest that [TIMP-2]·[IGFBP7] is not suitable for diagnostic of HRS and prediction of therapy response, but there might be evidence for prognostic value of [TIMP-2]·[IGFBP7] in regard to mortality of liver cirrhosis patients.     

IGFBP7 regulates sepsis-induced acute kidney injury through ERK1/2 signaling

IGFBP7 as an early biomarker has been used to identify patients at risk of developing acute kidney injury (AKI). Nevertheless, its role in AKI remains obscure. The aim of our study is to determine the role and mechanism of IGFBP7 in lipopolysaccharide (LPS)-induced HK-2 cells in vitro and on sepsis-induced AKI by cecal ligation and puncture (CLP) in vivo. Here, we identified that IGFBP7 expression was increased in patients with AKI and HK-2 cells with LPS (1, 2, and 5 μg/mL) induction. HK-2 cells with LPS induction showed cell cycle arrest at G1-G0 phases and cell apoptosis and activated ERK1/2 parallel with the changes in the proteins belonging to the ERK1/2 pathway, including Cyclin D1, P21, Bax, and Bcl-2, which were inhibited by the IGFBP7 knockdown. Moreover, IGFBP7 overexpression significantly induced cell cycle arrest at G1-G0 phases and cell apoptosis of HK-2 cells, which were inhibited by PD98509, an ERK1/2 signaling inhibitor. IGFBP7 knockdown effectively alleviated the severity of the renal injury, evidenced by decreases in the urinary levels of creatinine, blood urea nitrogen, and albumin, cell apoptosis, and activation of ERK1/2 signaling in CLP mice. Taken together, our findings indicate that IGFBP7 regulates sepsis-induced AKI through ERK1/2 signaling.     

Improving clinical prediction rules in acute kidney injury with the use of biomarkers of cell cycle arrest: a pilot study

Introduction: Early recognition of patients developing acute kidney injury (AKI) is of considerable interest, we report the first use of a combination of a clinical prediction rule with a biomarker in emergent adult medical patients to improve AKI recognition.

Methods: Single-centre prospective pilot study of medical admissions without AKI identified as high risk by a clinical prediction rule. Urine samples were obtained and tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) – biomarkers associated with cell cycle arrest, were measured.

Outcome: Creatinine-based KDIGO hospital-acquired AKI (HA-AKI).

Results: Of 69 patients recruited, HA-AKI developed in 13% (n?=?9), in whom biomarker values were higher (median 0.43 (interquartile range (IQR) 0.21–1.25) vs. 0.07 (0.03–0.16) in cases without (p?=?0.008). Peak rise in creatinine was higher in biomarker positive cases (median 30?μmol/L (7–72) vs. 1?μmol/L (0–16), p?=?0.002). AUROC was 0.78 (95% CI 0.57–0.98). At the suggested cut-off (0.3) sensitivity for predicting AKI was 78% (95% CI 40–97%), specificity 89% (78–95%), positive predictive value 50% (31–69%) and negative predictive value 96% (89–99%).

Discussion: Addition of a urinary biomarker allows exclusion of a significant number of patients identified to be at higher risk of AKI by a clinical prediction rule.     

IGFBP7 contributes to epithelial-mesenchymal transition of HPAEpiC cells in response to radiation

Radiation-induced lung injury (RILI) frequently occurs in patients with thoracic malignancies. In response to radiation, alveolar epithelial cells (AEC) undergo epithelial-mesenchymal transition (EMT) and contribute to the pathogenesis of RILI. Insulin-like growth factor binding protein 7 (IGFBP7) is reported as a downstream mediator of transforming growth factor-β1 (TGF-β1) pathway, which plays a crucial role in radiation-induced EMT. In the present study, the levels of IGFBP7 and TGF-β1 were simultaneously increased in experimental RILI models and radiation-treated AEC (human pulmonary alveolar epithelial cells [HPAEpic]). The expression of IGFBP7 in radiation-treated HPAEpic cells was obviously inhibited by the specific inhibitor of TGF-β receptor antagonist SB431542 and TGF-β1 neutralizing antibody, and time-dependently enhanced by TGF-β1 treatment. Moreover, IGFBP7 knockdown significantly attenuated the effects of radiation on morphology change, cell migration, expression of EMT-related markers (E-cadherin, α-SMA, and Vimentin), and phosphorylation of extracellular-signal-regulated kinase (ERK). The effects of IGFBP7 overexpression on the expression of EMT-related markers were partially reversed by the ERK inhibitor PD98059. In conclusion, IGFBP7, was enhanced by TGF-β1, may be involved in radiation-induced EMT of AEC via the ERK signaling pathway, thus contributing to the pathogenesis of RILI.     

Use of an extended KDIGO definition to diagnose acute kidney injury in patients with COVID-19: A multinational study using the ISARIC–WHO clinical characterisation protocol

BackgroundAcute kidney injury (AKI) is one of the most common and significant problems in patients with Coronavirus Disease 2019 (COVID-19). However, little is known about the incidence and impact of AKI occurring in the community or early in the hospital admission. The traditional Kidney Disease Improving Global Outcomes (KDIGO) definition can fail to identify patients for whom hospitalisation coincides with recovery of AKI as manifested by a decrease in serum creatinine (sCr). We hypothesised that an extended KDIGO (eKDIGO) definition, adapted from the International Society of Nephrology (ISN) 0by25 studies, would identify more cases of AKI in patients with COVID-19 and that these may correspond to community-acquired AKI (CA-AKI) with similarly poor outcomes as previously reported in this population.Methods and findingsAll individuals recruited using the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC)–World Health Organization (WHO) Clinical Characterisation Protocol (CCP) and admitted to 1,609 hospitals in 54 countries with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection from February 15, 2020 to February 1, 2021 were included in the study. Data were collected and analysed for the duration of a patient’s admission. Incidence, staging, and timing of AKI were evaluated using a traditional and eKDIGO definition, which incorporated a commensurate decrease in sCr. Patients within eKDIGO diagnosed with AKI by a decrease in sCr were labelled as deKDIGO. Clinical characteristics and outcomes—intensive care unit (ICU) admission, invasive mechanical ventilation, and in-hospital death—were compared for all 3 groups of patients. The relationship between eKDIGO AKI and in-hospital death was assessed using survival curves and logistic regression, adjusting for disease severity and AKI susceptibility. A total of 75,670 patients were included in the final analysis cohort. Median length of admission was 12 days (interquartile range [IQR] 7, 20). There were twice as many patients with AKI identified by eKDIGO than KDIGO (31.7% versus 16.8%). Those in the eKDIGO group had a greater proportion of stage 1 AKI (58% versus 36% in KDIGO patients). Peak AKI occurred early in the admission more frequently among eKDIGO than KDIGO patients. Compared to those without AKI, patients in the eKDIGO group had worse renal function on admission, more in-hospital complications, higher rates of ICU admission (54% versus 23%) invasive ventilation (45% versus 15%), and increased mortality (38% versus 19%). Patients in the eKDIGO group had a higher risk of in-hospital death than those without AKI (adjusted odds ratio: 1.78, 95% confidence interval: 1.71 to 1.80, p-value < 0.001). Mortality and rate of ICU admission were lower among deKDIGO than KDIGO patients (25% versus 50% death and 35% versus 70% ICU admission) but significantly higher when compared to patients with no AKI (25% versus 19% death and 35% versus 23% ICU admission) (all p-values <5 × 10⁻⁵). Limitations include ad hoc sCr sampling, exclusion of patients with less than two sCr measurements, and limited availability of sCr measurements prior to initiation of acute dialysis.ConclusionsAn extended KDIGO definition of AKI resulted in a significantly higher detection rate in this population. These additional cases of AKI occurred early in the hospital admission and were associated with worse outcomes compared to patients without AKI.

Marina Wainstein and colleagues examine acute kidney injury (AKI) incidence, severity, and outcomes among patients with COVID-19 using both a traditional and extended definition of AKI.     

Expression of IGFBP7 mRNA in Corticotrophs in the Anterior Pituitary of Adrenalectomized Rats

The number of corticotrophs increases in the anterior pituitary (AP) gland in adrenalectomized (AdX) rats. In this study, aimed at identifying the growth factor implicated in this proliferation, we analyzed proteins secreted from a cDNA library of the AP of AdX rats, using the signal sequence trap method. A PCR analysis of several cDNAs that coded for insulin-like growth factor binding protein (IGFBP) 5, IGFBP7, and vacuolar H⁺-ATPase accessory subunit Ac45 revealed an increased and decreased expression level of IGFBP7 mRNA in the AP of AdX rats and AdX rats injected with dexamethasone, respectively. IGFBP7 mRNA was predominately expressed in the corticotrophs of the APs of both sham-operated and AdX rats. The AP of AdX rats contained an increased number of IGFBP7 mRNA–expressing cells and corticotrophs compared with that of sham-operated rats, but the ratio of IGFBP7 mRNA–positive corticotrophs per total number of corticotrophs did not significantly change in either group. Histochemical analysis of labeled proliferating cell nuclear antigen (PCNA) and sex-determining region Y box-2 (SOX2) revealed the presence of several PCNA-positive signals and the absence of SOX2 cells among the corticotrophs, suggesting that IGFBP7 mRNA–expressing corticotrophs are derived from in situ corticotrophs and that they increase in number as corticotrophs increase. The possible roles of IGFBP7 in the corticotrophs are also discussed. (J Histochem Cytochem 58:969–978, 2010)     

Combined Biomarker Analysis for Risk of Acute Kidney Injury in Patients with ST-Segment Elevation Myocardial Infarction

Background

Acute kidney injury (AKI) complicating ST-segment elevation myocardial infarction (STEMI) increases subsequent morbidity and mortality. We combined the biomarkers of heart failure (HF; B-type natriuretic peptide [BNP] and soluble ST2 [sST2]) and renal injury (NGAL [neutrophil gelatinase-associated lipocalin] and cystatin C) in predicting the development of AKI in patients with STEMI undergoing primary percutaneous coronary intervention (PCI).

Methods and Results

From March 2010 to September 2013, 189 STEMI patients were sequentially enrolled and serum samples were collected at presentation for BNP, sST2, NGAL and cystatin C analysis. 37 patients (19.6%) developed AKI of varying severity within 48 hours of presentation. Univariate analysis showed age, Killip class ≥2, hypertension, white blood cell counts, hemoglobin, estimated glomerular filtration rate, blood urea nitrogen, creatinine, and all the four biomarkers were predictive of AKI. Serum levels of the biomarkers were correlated with risk of AKI and the Acute Kidney Injury Network (AKIN) stage and all significantly discriminated AKI (area under the receiver operating characteristic [ROC] curve: BNP: 0.86, sST2: 0.74, NGAL: 0.75, cystatin C: 0.73; all P < 0.05). Elevation of ≥2 of the biomarkers higher than the cutoff values derived from the ROC analysis improved AKI risk stratification, regardless of the creatine level (creatinine < 1.24 mg/dL: odds ratio [OR] 11.25, 95% confidence interval [CI] 1.63-77.92, P = 0.014; creatinine ≥ 1.24: OR 15.0, 95% CI 1.23-183.6, P = 0.034).

Conclusions

In this study of STEMI patients undergoing primary PCI, the biomarkers of heart failure (BNP and sST2) and renal injury (NGAL and cystatin C) at presentation were predictive of AKI. High serum levels of the biomarkers were associated with an elevated risk and more advanced stage of AKI. Regardless of the creatinine level, elevation of ≥2 of the biomarkers higher than the cutoff values indicated a further rise in AKI risk. Combined biomarker approach may assist in risk stratification of AKI in patients with STEMI.     

The Circ_35953 induced by the NF-κB mediated the septic AKI via targeting miR-7219-5p/HOOK3 and IGFBP7 axis

A few studies suggested that CircRNAs were involved in the development of septic AKI. However，the role and regulation mechanism of CircRNA_35953 in septic AKI remains unclear. Here, we found that Circ_35953 was induced by LPS via activation of NF-κB signal in BUMPT cells. Functionally, Circ_35953 mediated the LPS induced the apoptosis in BUMPT cells. Moreover, we demonstrated that Circ_35953 sponged miR-7219-5p to upregulate the expression of HOOK3 and IGFBP7. Finally, we verified that knock down of Circ_35953 alleviated the progression of CLP-induced AKI via targeting the miR-7219-5p/HOOK3 and IGFBP7 signal. Collectively, the data suggested that Circ_35953 /miR-7219-5p/HOOK3 and IGFBP7 axis mediated the septic AKI, which also revealed a potential mechanism of septic AKI.     

Incidence and Mortality of Acute Kidney Injury after Myocardial Infarction: A Comparison between KDIGO and RIFLE Criteria

Background

Acute kidney injury (AKI) increases the risk of death after acute myocardial infarction (AMI). Recently, a new AKI definition was proposed by the Kidney Disease Improving Global Outcomes (KDIGO) organization. The aim of the current study was to compare the incidence and the early and late mortality of AKI diagnosed by RIFLE and KDIGO criteria in the first 7 days of hospitalization due to an AMI.

Methods and Results

In total, 1,050 AMI patients were prospectively studied. AKI defined by RIFLE and KDIGO occurred in 14.8% and 36.6% of patients, respectively. By applying multivariate Cox analysis, AKI was associated with an increased adjusted hazard ratio (AHR) for 30-day death of 3.51 (95% confidence interval [CI] 2.35–5.25, p<0.001) by RIFLE and 3.99 (CI 2.59–6.15, p<0.001) by KDIGO and with an AHR for 1-year mortality of 1.84 (CI 1.12–3.01, p = 0.016) by RIFLE and 2.43 (CI 1.62–3.62, p<0.001) by KDIGO. The subgroup of patients diagnosed as non-AKI by RIFLE but as AKI by KDIGO criteria had also an increased AHR for death of 2.55 (1.52–4.28) at 30 days and 2.28 (CI 1.46–3.54) at 1 year (p<0.001).

Conclusions

KDIGO criteria detected substantially more AKI patients than RIFLE among AMI patients. Patients diagnosed as AKI by KDIGO but not RIFLE criteria had a significantly higher early and late mortality. In this study KDIGO criteria were more suitable for AKI diagnosis in AMI patients than RIFLE criteria.     

Seroprevalence of Fecal-Oral Transmitted Hepatitis A and E Virus Antibodies in Burkina Faso

Hepatitis A virus (HAV) and hepatitis E virus (HEV) infections occur chiefly as a result of unhygienic conditions. The purpose of this study was to assess the seroprevalence of antibodies to both viruses in central Burkina Faso in the absence of a recorded hepatitis epidemic. Serum samples from 178 blood donors (131 males and 47 females) and from 189 pregnant women were collected from November 2010 to March 2012, at blood banks and medical centers in Burkina Faso. An immunochromatography test was used to screen for Anti-HAV IgM and IgG in a subgroup of 91 blood donors and 100 pregnant women. The seroprevalence of anti-HAV IgG was 14.3% [CI95, 7.1–21.4%] for all blood donors and 23% [CI95, 14.8–31.2%] for pregnant women. Anti-HEV IgG were detected using the ELISA kits Dia.pro and Wantai and were found in 19.1% [CI95, 13.3–24.9%] of the blood donors and 11.6% [CI95, 7.1–16.2%] of the pregnant women. The seroprevalences of anti-HAV and anti-HEV IgGs did not differ significantly between men and women blood donors. Anti-HAV IgM was detected in 3.3% of the blood donors and in 2% of the pregnant women. These findings for asymptomatic individuals indicate that the HAV and HEV circulate at low but significant levels. This is the first evaluation of the acute hepatitis virus burden in Burkina Faso and the underlying epidemiologic status of the population.     

IGFBP7在甲状腺乳头状癌中的表达及意义

目的观察胰岛素样生长结合蛋白-7(IGFBP7)在甲状腺乳头状癌中的表达及意义。方法对87例甲状腺乳头癌(PTC)组织及癌旁组织(PeT)进行IGFBP7、Ki67、p53免疫组织化学分析,其中10例提取蛋白用半定量western blot方法进行IGFBP7表达水平分析。结果 (1)IGFBP7免疫组化显示,PTC癌组织IGFBP7阳性率达78.16%(68/87),明显高于癌旁组织的31.03%(27/87)(P0.05);(2)Western blot灰度值比较,癌组织IGFBP7表达水平显著高于癌旁组织(t=2.875,P0.05);(3)Ki67、p53与IGFBP7相关性分析显示,p53表达水平与IGFBP7表达水平呈显著正相关性(r=0.261,P0.05),而Ki67表达水平与IGFBP7表达水平无相关性(r=0.148,P=0.170);(4)高水平表达的IGFBP7与PTC淋巴结转移高度相关(r=0.238,P0.05)。结论 IGFBP7表达异常增高可能与甲状腺乳头状癌发生及发展有关,有望成为诊断PTC的一项新型的生物标记物。     

Serosurvey of anti-Toxocara antibodies and risk factors in adolescent and adult pregnant women of southeastern Brazil

Toxocariasis is worldwide endemic parasitic anthropozoonosis with high risk to those in in vulnerable populations and particularly during pregnancy and childhood. Although the prevalence of anti-Toxocara spp. antibodies has been extensively studied, risk factors of pregnant women of different ages remains to be established. This study was designed to i) assess the presence of anti-Toxocara spp. antibodies in pregnant women that presented to the public health system in a city of southeastern Brazil, and ii) determine the risk factors for toxocariasis in adolescent and adult pregnant women. This cross-sectional study included 280 pregnant women (71 aged up to and including 17 years [adolescents] and 209 aged 18 years and older [adults]). Pregnant women voluntarily agreed to complete a socioeconomic questionnaire and provide serum samples. Anti-Toxocara IgG antibodies were screened by Enzyme-Linked Immunosorbent Assay (ELISA). Univariable and multivariable logistic regression models were performed to assess the risks for toxocariasis. Overall, 20.7% of pregnant women were seropositive (33.8% of adolescents and 16.3% of adults). Prevalence in pregnant adolescents was 2.6-fold higher than in adults (Odds ration [OR]: 2.63; 95% CI: 1.42–4.86, p = 0.003). Multivariate analysis revealed that contact with soil (p = 0.01; OR = 4.76) and being in the first trimester of pregnancy (p = 0.03; OR = 0.17) had significantly greater risk of toxocariasis for adolescents, and attainment of elementary through middle school education level (p = 0.05; OR = 8.33) was a risk factor in adult pregnant women. Toxocariasis is likely underreported and neglected in adolescent pregnant women; this age group should always be monitored for toxocariasis and correspondent clinical signs, particularly at late pregnancy.     

Assessment of the biological variation of plasma tissue inhibitor of metalloproteinases-1

BACKGROUND: Tissue inhibitor of metalloproteinases-1 (TIMP-1) measurements in plasma may be useful for the early detection and prognosis of colorectal cancer (CRC). Data on analytical performance and normal intra- and interindividual biological variation are required in order to interpret the utility of TIMP-1 in CRC. The aim of this study was to establish the biological and analytical variation of plasma TIMP-1 in volunteers. MATERIAL AND METHODS: Three separate studies were undertaken. 1: Plasma was collected from 23 volunteers 6 times within a 3-week period, first in September 2004 (round [R] 1), then repeated in May 2005 (R2) and May 2006 (R3) in the same group of individuals. TIMP-1 levels were determined by the MAC15 ELISA assay and with the Abbott ARCHITECT i2000 Immunoanalyzer. 2: Circadian variation was evaluated in plasma collected 7 times within a 24-hour period (n=16). 3: Effects of physical exercise were evaluated in plasma collected before and after bicycling (n=14). In studies 2 and 3 TIMP-1 levels were determined with the MAC15 ELISA assay only. RESULTS: A significant correlation between TIMP-1 MAC15 and ARCHITECT i2000 was shown (rs=0.78, p<0.002), with consistently higher levels being detected by the ARCHITECT i2000. Median levels of TIMP-1 (ARCHITECT) at 8 a.m. in each round were 74.9 ng/mL (range 65.7-89.9) (R1), 87.3 ng/mL (range 72.7-127.9) (R2), and 81.9 ng/mL (range 66.8-113.6) (R3). The within-subject variation was 10.7%, the variation between rounds was 7.4%, and the intraclass correlation was 46.2%. Comparison between the 3 rounds and time of collection showed that TIMP-1 values decreased by 11% after storage for more than 16 months (p=0.0002). A systematic circadian variation in plasma TIMP-1 levels was not observed (p=0.17). No significant variation of plasma TIMP-1 was found in relation to physical exercise (p=0.92 [global test]). CONCLUSION: Levels of plasma TIMP-1 in volunteers show limited circadian, day-to-day, week-to-week and season-to-season variation. In addition, physical exercise has no impact on plasma TIMP-1 levels. Possible storage-dependent decreases in plasma TIMP-1 levels warrant further investigation.     

Maternal Subclinical Hypothyroidsm and Gestational Diabetes Mellitus: A Meta-Analysis

ObjectiveThe association between subclinical hypothyroidism (SCH) and gestational diabetes mellitus (GDM) is controversial. This review evaluates whether the risk of GDM is different in pregnant women with SCH compared to euthyroid pregnant women.MethodsA computerized search of the MEDLINE and EMBASE databases was conducted from their inceptions to July 2013 and was complemented with the perusal of the reference sections of the retrieved articles. Prespecified criteria were applied to assess eligibility, and standard meta-analytic methodology was employed for evidence synthesis.ResultsSix cohort studies, reporting data on 35,350 pregnant women (1,216 women with SCH), were identified. The risk of GDM in pregnant women with SCH was found to be substantially higher compared to euthyroid pregnant women (5 studies, pooled unadjusted odds ratio [OR]: 1.35, 95% confidence interval [CI]: 1.05-1.75, I²: 41%, Harbord test P = .44). Similarly, the risk of GDM was estimated to be significantly higher in pregnant women with SCH when using adjusted estimates (3 studies, pooled adjusted OR: 1.39, 95% CI: 1.07-1.79, I²: 0%). Neither finding remained significant in sensitivity analyses.ConclusionA modestly increased risk of GDM might be present in pregnant women with SCH compared to euthyroid pregnant women. Assuming a 5% baseline risk of GDM and that SCH increases the risk of GDM by 50% (in odds) compared to a euthyroid population, then there would be 1 extra case of GDM in every 43 pregnant women with SCH. This preliminary finding warrants further investigation. (Endocr Pract. 2014;20:703-714)     

Evaluation of a recombinant rhoptry protein 2 enzyme-linked immunoassay for the diagnosis of toxoplasmosis acquired during pregnancy

The aim of this study was to evaluate an enzyme-linked immunoassay with recombinant rhoptry protein 2 (ELISA-rROP2) for its ability to detectToxoplasma gondii ROP2-specific IgG in samples from pregnant women. The study included 236 samples that were divided into groups according to serological screening profiles for toxoplasmosis: unexposed (n = 65), probable acute infection (n = 48), possible acute infection (n = 58) and exposed to the parasite (n = 65). When an indirect immunofluorescence assay forT. gondii-specific IgG was considered as a reference test, the ELISA-rROP2 had a sensitivity of 61.8%, specificity of 62.8%, predictive positive value of 76.6% and predictive negative value of 45.4% (p = 0.0002). The ELISA-rROP2 reacted with 62.5% of the samples from pregnant women with probable acute infection and 40% of the samples from pregnant women with previous exposure (p = 0.0180). Seropositivity was observed in 50/57 (87.7%) pregnant women with possible infection. The results underscored that T. gondii rROP2 is recognised by specific IgG antibodies in both the acute and chronic phases of toxoplasmosis acquired during pregnancy. However, the sensitivity of the ELISA-rROP2 was higher in the pregnant women with probable and possible acute infections and IgM reactivity.