Detection of miR-122 by fluorescence real-time PCR in blood from patients with chronic hepatitis B and C infections.

BACKGROUND: This study aims to determine whether relative miR-122 levels in peripheral blood are correlated with chronic hepatitis B (CHB) and chronic hepatitis C (CHC) virus infection and viral replication to determine whether miR-122 can be a new marker for liver injury. METHODS: MicroRNA (miRNA) was extracted from the peripheral blood of 20 CHB patients, 20 CHC patients, and 20 healthy controls. The levels of miR-122 were determined using fluorescence real-time reverse transcription PCR. Then, the associations of miR-122 with CHB and CHC were analyzed, and its correlation with other markers of liver function and viral replication were determined. RESULTS: The expression level of miR-122 in patients with CHB was significantly higher when compared to subjects in the control group (P = 0.007) or CHC patients (P = 0.005). Furthermore, the miR-122 level in patients with CHC was somewhat higher when compared to healthy controls (66% higher), but the difference was not statistically significant (P = 0.229). MiR-122 levels were significantly correlated with ALT (correlation coefficient [R] = 0.7, P < 0.001), AST (R = 0.71, P < 0.001), and HBV NA (R = 0.9, P < 0.001). The regression analysis indicated that the AUC of miR-122 levels in the diagnosis of CHB was 0.87, with a sensitivity of 0.8 and a specificity of 0.8. CONCLUSION: MiR-122 can be used to distinguish healthy persons and patients with CHB infection with high sensitivity and specificity. These present findings presented that the complex and context-specific associations of miR-122 with liver diseases, suggesting that this may be a promising marker for liver injury.

Quantitative Analysis of Hepatic Toxicity in Rats Induced by Inhalable Silica Nanoparticles Using Acoustic Radiation Force Imaging.

OBJECTIVES: The purposes of this study were to verify whether inhalable silicon dioxide (SiO2 ) nanoparticles could induce hepatic injury and to investigate the relationship between the exposure time and SiO2 nanoparticle dosage by using acoustic radiation force impulse imaging (ARFI). METHODS: A total of 72 rats were randomly separated into 9 groups with 8 in each: blank control group, 0.9% normal saline group, polyacrylate (PPE) group, 25%, 50%, and 100% SiO2 groups, and 25%, 50%, and 100% SiO2 /PPE groups with inhaled SiO2 nanoparticle concentrations similar to the SiO2 groups. After successful modeling and design, the hepatic shear wave velocity (SWV) values of the 9 groups were obtained on days 3, 7, 14, 21, and 28 by using ARFI, and the intragroup and intergroups differences in the SWVs were compared. The serum alanine aminotransferase (ALT) and aspartate aminotransferase were tested and compared on day 28. Hepatic tissues were collected for histologic observation on day 28. RESULTS: The pathologic results verified that inhalable SiO2 nanoparticles could induce hepatic injury. Compared with the control group, the hepatic SWV and serum ALT values in the SiO2 groups and SiO2 /PPE groups were elevated (P < .05). The dosage and exposure time of SiO2 played a key role in the elevation of the SWV in the SiO2 and SiO2 /PPE groups. The correlation between the ALT level and SWV was significant on day 28 (P < .05). CONCLUSIONS: Inhalable SiO2 nanoparticles and SiO2 /PPE were able to induce hepatic injury in rats. Using ARFI to evaluate hepatic toxicity induced by SiO2 nanoparticles was effective in this study.

Circular RNA SMARCA5 Promotes a Poor Prognosis and Radiotherapy Resistance for Patients with Hepatocellular Carcinoma.

OBJECTIVE: The involvement of Circular RNA SMARCA5 (cSMARCA5) in several types of cancer has been reported; however, its role in hepatocellular carcinoma (HCC) is unclear. The presented research aimed to explore the expression level of cSMARCA5 in HCC tissues and evaluate the association between cSMARCA5, prognosis, and radiotherapy resistance for patients with HCC. METHODS: This study was designed as a case controlled study and enrolled 106 HCC patients. HCC and paired non-tumor samples were collected from HCC patients. Gene expression was analyzed by RT-qPCR. The association between the expression level of cSMARCA5 and prognosis value and radiotherapy resistance for patients with HCC was analyzed by Kaplan-Meier survival curve and Multivariate Cox analysis. RESULTS: Compared to paracancerous tissue, cSMARCA5 demonstrated higher expression in the tumor tissues (p<0.0001).Higher expression of cSMARCA5 is a risk factor in 3-year overall survival (OS) for HCC patients (HR=1.798, 95%CI: 1.165~3.231, p=0.0321). Multivariate analysis showed that higher expression of cSMARCA5 was related to PVTT (HR=2.136, 95%CI: 1.130~5.218), AFP (>400ng/ml) (HR=2.335, 95%CI: 1.247~5.661), tumor size (>5cm) (HR=3.017, 95%CI: 1.477~5.659), poor histopathologic grading (HR=3.344, 95%CI: 2.175~6.143), and multiple tumor number (HR=2.875, 95%CI: 1.453~3.884). We also found that radiotherapy resistance was related to AFP (>400ng/ml) (OR=2.125, 95%CI: 1.015~3.348), tumor size (>5cm) (OR=2.857, 95%CI: 1.665~4.978), poor histopathologic grading (OR=2.463, 95%CI: 1.389~4.446), multiple tumor number (OR=2.332, 95%CI: 1.538~3.887), and high expression of cSMARCA5 (OR=3.574, 95%CI: 1.663~5.932). CONCLUSION: CircRNA-SMARCA5 is significantly increased in HCC tissues and promotes radiotherapy resistance. More importantly, higher expression level of cSMARCA5 is related to a poorer 3-year OS for patients with HCC.

Silica nanoparticles induce pulmonary damage in rats via VEGFC/D-VEGFR3 signaling-mediated lymphangiogenesis and remodeling.

Silica nanoparticles (SiNPs) are widely used as drug carriers for improving drug delivery and retention. The lungs are highly sensitive to the toxicity of SiNPs entering the respiratory tract. Furthermore, pulmonary lymphangiogenesis, which is the growth of lymphatic vessels observed during multiple pulmonary diseases, plays a vital role in promoting the lymphatic transport of silica in the lungs. However, more research is required on the effects of SiNPs on pulmonary lymphangiogenesis. We investigated the effect of SiNP-induced pulmonary toxicity on lymphatic vessel formation in rats and evaluated the toxicity and possible molecular mechanisms of 20-nm SiNPs. Saline containing 3.0, 6.0, and 12.0 mg/kg of SiNPs was instilled intrathecally into female Wistar rats once a day for five days, then sacrificed on day seven. Lung histopathology, pulmonary permeability, pulmonary lymphatic vessel density changes, and the ultrastructure of the lymph trunk were investigated using light microscopy, spectrophotometry, immunofluorescence, and transmission electron microscopy. CD45 expression in lung tissues was determined using immunohistochemical staining, and protein expression in the lung and lymph trunk was quantified using western blotting. We observed increased pulmonary inflammation and permeability, lymphatic endothelial cell damage, pulmonary lymphangiogenesis, and remodeling with increasing SiNP concentration. Moreover, SiNPs activated the VEGFC/D-VEGFR3 signaling pathway in the lung and lymphatic vessel tissues. SiNPs caused pulmonary damage, increased permeability and resulted in inflammation-associated lymphangiogenesis and remodeling by activating VEGFC/D-VEGFR3 signaling. Our findings provide evidence for SiNP-induced pulmonary damage and a new perspective for the prevention and treatment of occupational exposure to SiNPs.

Broken thermometer in hand: mercury elevation caused by improper debridement.

BACKGROUND: Mercury exposure from broken thermometers is still common in China. CASE REPORT: Here, we report a 2-year-old girl with elevated mercury concentrations in her blood and urine due to improper debridement after pricked by a broken thermometer. She underwent the first debridement at a local hospital, but radiographs showed a dot-like mercury deposit turned into multiple dispersed beads in her wrist tissue. Although the patient had no signs or symptoms of mercury poisoning, her blood and urinary mercury concentrations were significantly elevated. Several radio-opaque densities remained in her hand until a second debridement. At 2 years follow-up, her mercury concentrations in blood and urine and her hand radiograph were normal. CONCLUSIONS: Careful debridement after injury by broken thermometer is important in order to remove mercury in tissues and to prevent its dispersion and further absorption.

Toxic Nephropathy Secondary to Chronic Mercury Poisoning: Clinical Characteristics and Outcomes.

Introduction: Kidney disease secondary to mercury poisoning has not been well documented and is often misdiagnosed and mistreated. Methods: We performed a retrospective analysis of patients diagnosed with having mercury poisoning over a 6-year period between July 2013 and June 2019. Demographics, clinical measures, renal pathologic examinations, treatments, and outcomes were compared between patients with kidney disease and those without kidney disease. Results: Of the 172 patients with mercury poisoning, 46 (26.74%) had renal damage. Among the 46 patients, 41 (89.13%) presented nephrotic syndrome, and 5 (10.87%) showed proteinuria alone. The pathologic abnormality associated with kidney disease caused by mercury poisoning was mainly membranous nephropathy (18 of 35 patients, 51.43%). Among 41 patients with nephrotic syndrome, 25 were treated with chelation therapy alone and 12 with mercury chelation therapy and glucocorticoids. The remaining 4 patients were treated with chelation therapy, glucocorticoids, and immunosuppressive therapies. The overall effective rate was 97.5% (40 patients). There was no significant difference in complete remission rate among the 3 treatment methods (P < 0.05). Conclusion: The main clinical manifestation of kidney disease secondary to chronic mercury poisoning was nephrotic syndrome, which was reflected in pathologic examinations as membranous nephropathy. Kidney disease to chronic mercury poisoning is prone to misdiagnosis and missed diagnosis. Chelation therapy is the main treatment, and the prognosis is good. Patients with severe condition can be supplemented with glucocorticoid.

Nanomaterials in humans: identification, characteristics, and potential damage.

Nanomaterials are increasingly being used for commercial purposes. However, concerns about the potential risks of exposure to humans have been raised. We previously reported unusual pulmonary disease and death in a group of patients with occupational exposure to spray paint. However, the nanoparticle and chemical composition of the exposure was not fully described. The present study aimed to isolate and identify the nanoparticles observed in the patients' biopsies and report the potential deleterious effects to human lungs using electron microscopy. Using electron microscopy and energy dispersive x-ray analysis, silica nanoparticles were identified and characterized mainly in macrophages, pulmonary microvessels, vascular endothelial cells, microlymphatic vessels, pleural effusions, and a few in alveolar epithelial cells and pulmonary interstitial tissue (with no microscale particles present). Notably, damage to alveolar epithelial cells, macrophages, vascular endothelial cells, and the blood-gas barrier was observed. Given the well-documented toxicity of microscale silica, it is possible that these silica nanoparticles may have contributed in part to the illness reported in these workers. Such a possibility supports the adoption of controls and prevention strategies to minimize inhalation of nanoparticles by workers, and it highlights the urgent need and the importance of the nanosafety study in humans.

Nanoexposure, unusual diseases, and new health and safety concerns.

Accumulating studies in animals have shown that nanoparticles could cause unusual rapid lung injury and extrapulmonary toxicity. Whether exposure of workers to nanoparticles may result in some unexpected damage as seen in animals is still a big concern. We previously reported findings regarding a group of patients exposed to nanoparticles and presenting with an unusual disease. The reported disease was characterized by bilateral chest fluid, pulmonary fibrosis, pleural granuloma, and multiorgan damage and was highly associated with the nanoparticle exposure. To strengthen this association, further information on exposure and the disease was collected and discussed. Our studies show that some kinds of nanomaterials, such as silica nanoparticles and nanosilicates, may be very toxic and even fatal to occupational workers exposed to them without any effective personal protective equipment. More research and collaborative efforts on nanosafety are required in order to prevent and minimize the potential hazards of nanomaterials to humans and the environment.

Multiply organ dysfunction syndrome due to tramadol intoxication alone.

Tramadol is a synthetic, centrally acting analgesic for the treatment of moderate to severe pain. It is widely used because of its efficacy and safety. A normal-dose tramadol has less adverse effects than other opioids. Multiply organ dysfunction syndrome due to tramadol intoxication is rare.We present a case of 19-year-old male patient who had multiply organ dysfunction syndrome due to oral tramadol alone. With a history of tramadol abuse for 6 months, the patient was found unconsciousness in bed 8 hours before hospitalization. A toxicologic analysis showed a tramadol blood concentration of 9.5 mg/L without toxic levels of other drugs. The patient developed deep coma, acute respiratory distress syndrome, hepatic and renal dysfunction,and shock in the first 24 hours after admission. With mechanical ventilation, hemoperfusion, and other supportive therapies, his overall status gradually improved and he was discharged 23 days later.

Mercury Poisoning Presenting With Hypertension: Report of 2 Cases.

BACKGROUND: Mercury poisoning can cause damage to multiple organs. Secondary hypertension, which is usually misdiagnosed and mistreated, has been rarely reported in cases of mercury poisoning. METHODS: We herein present 2 cases of hypertension as the main manifestation of mercury poisoning. RESULTS: Case 1 involved a 42-year-old man with blood pressure of 230/190 mm Hg and urinary mercury level of 131.54 µmol/molCr. The patient had been repeatedly exposed to mercury at his workplace and had been admitted to our department many times. His hypertension quickly normalized after every chelation treatment. Case 2 involved a 10-year-old girl with hypertension (150/110 mm Hg), rash, and convulsions. She was found to have elevated blood levels of renin, angiotensin II, and aldosterone as well as an elevated urinary mercury level. Her hypertension recovered soon after chelation treatment. CONCLUSIONS: Mercury poisoning can cause secondary hypertension as the main clinical manifestation or together with multiorgan damage. Renin-angiotensin system activation may be involved in the occurrence and development of hypertension.

A Pleural Effusion Model in Rats by Intratracheal Instillation of Polyacrylate/Nanosilica.

Pleural effusion is a prevalent clinical finding of many pulmonary diseases. Having a useful animal pleural effusion model is very important to study these pulmonary diseases. Previous pleural effusion models paid more attention to biological factors rather than nanoparticles in the environment. Here, we introduce a model to make pleural effusion in rats by intratracheal instillation of polyacrylate/nanosilica, and a method of nanoparticle isolation in the pleural effusion. By intratracheal instillation of polyacrylate/nanosilica with concentrations of 3.125, 6.25 and 12.5 mg/kg∙mL, the pleural effusion in rats presented on day 3, peaked at days 7-10 in 6.25 and 12.5 mg/kg∙mL groups, then slowly decreased and disappeared on day 14. When the concentration of polyacrylate/nanosilica increased, the pleural effusion is produced more and faster. This pleural fluid was detected by ultrasound examination or CT chest scanning and confirmed by dissection of rats. Silica nanoparticles were observed in the rats' pleural effusion by transmission electron microscope. These results showed that the exposure to polyacrylate/nanosilica leads to the induction of pleural effusion, which was consistent with our previous report in humans. Additionally, this model is beneficial for the further study of nanotoxicology and the pleural effusion diseases.

[Clinical study on pneumoconiosis with pulmonary thromboembolism].

OBJECTIVE: To probe into the clinical features and the rescue of pneumoconiosis with pulmonary thromboembolism (PTE). METHODS: 26 patients with pneumoconiosis and PTE, male 16, female 10, were collected from June 2002 to June 2006 and 42 patients only with pneumoconiosis served as control. Tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), thrombomodulin (TM), plasma protein S, C (Ps, Pc), homocysteine (Hcy) were measured by the methods of ILISA, and antithrombin (AT-III) by chromo substrate method before and after the treatment of heparin. RESULTS: The average age of patients with pneumoconiosis and PTE was 66.0 +/- 11.9 years old. The number of patients with pneumoconiosis of degree 1, 2, 3 was 3, 16 and 7 respectively. After anticoagulant therapy of heparin, 23 were well improved, and 3 died of acute respiratory failure. Dyspnea, chest pain, hemoptysis, syncope were the conspicuous symptoms. The levels of D-Dimer (0.63 +/- 0.14 mg/L), TM (5.02 +/- 1.24 microg/L) were significantly higher than those of the control (P < 0.05), and significantly lower again after the treatment (P < 0.05). The level of AT-III (96.68 +/- 7.23%) was significantly lower than that of the control, and higher again after the treatment (P < 0.05). CONCLUSION: PTE is often developed in the elder patients with high degree of pneumoconiosis (> or = 2 degree). Clinical features are complicated and non-specific, with the high negative ratio of D-Dimer (7/26), high mortality and high complications of anticoagulant therapy.

Dimethyl fumarate accelerates wound healing under diabetic condition.

Impaired wound healing is a common complication among patients with diabetes mellitus (DM), resulting in high rates of disability and mortality. Recent findings highlighted the critical role of nuclear factor erythroid 2-related factor 2 (NRF2) - a master of cellular antioxidants scavenging excessive DM-induced free radicals - in accelerating diabetic wound healing. Dimethyl fumarate (DMF) is a potent NRF2 activator used for the treatment of multiple sclerosis. However, the effect of DMF on wound healing has not been determined. The present study investigated the effect of DMF on the diabetic and the non-diabetic wound healing in streptozotocin-induced diabetic mice and non-diabetic control mice. DMF activated NRF2 signaling under both conditions. Interestingly, DMF attenuated oxidative damage and inflammation, and accelerated wound closure in the diabetic mice. However, this effect was not observed in non-diabetic mice. Keratinocytes were treated with normal glucose (NG), high glucose (HG), or hydrogen peroxide (H2O2), in the presence or absence of DMF to assess the role of reactive oxygen species (ROS) - inducible in DM - in mediating DMF-induced protection. Both HG and H2O2 elevated ROS, oxidative damage, and inflammation, the effects of which were similarly blunted by DMF. However, in spite of the activation of NRF2, DMF lost this capability under the NG condition. The findings of this study demonstrate that ROS activate the protective effect of DMF on the diabetic wound healing.

SP600125 suppresses Keap1 expression and results in NRF2-mediated prevention of diabetic nephropathy.

c-Jun N-terminal kinase (JNK) contributes to the pathogenesis of diabetic nephropathy (DN). The JNK inhibitor SP600125 was reported to ameliorate DN. However, the mechanism remained unclear. We previously reported that SP600125 activated nuclear factor erythroid 2-related factor 2 (NRF2), a governor of the cellular antioxidant defense system, in the aortas of the diabetic mice. Given the critical role of NRF2 in preventing DN, the present study aimed to test whether or not NRF2 is required for SP600125's protection against DN. To test the role of NRF2 in SP600125's effect, streptozotocin-induced C57BL/6 wild-type (WT) and Nrf2-knockout (KO) diabetic mice were treated in the presence or absence of SP600125, for 24 weeks. To explore the mechanism by which SP600125 activates NRF2, mouse mesangial cells (MMCs) were treated with high glucose (HG), in the presence or absence of either SP600125 or JNK siRNA. SP600125 significantly attenuated the diabetes-induced renal oxidative stress, inflammation, fibrosis, pathological change and dysfunction in the WT, but not the Nrf2 KO mice. SP600125 inactivated JNK, inhibited kelch-like ECH-associated protein 1 expression, preserved NRF2 protein and facilitated its nuclear translocation in the kidneys of the WT mice, the effects of which were similarly produced by either SP600125 or JNK siRNA in HG-treated MMCs. Further, both SP600125 and JNK siRNA alleviated HG-induced mesangial oxidative stress and expression of inflammatory and fibrotic genes. The present study demonstrates that NRF2 is required for SP600125's protection against DN. SP600125 activates NRF2 possibly via inhibition of JNK-induced Keap1 expression.

Severe acute arsine poisoning treated by plasma exchange.

INTRODUCTION: Exposure to arsine gas can cause fatal hemolysis and multiorgan damage. Whole blood exchange transfusion and hemodialysis have been recommended to treat severe acute arsine poisoning, but are associated with significant complications and sub-optimal outcomes. Plasma exchange is another method of blood purification technique but there are no data on its use in acute arsine poisoning. This retrospective study evaluated the clinical and effects and arsenic clearance from the use of plasma exchange treatment of patients with acute arsine poisoning. METHODS: Data from patients with severe acute arsine poisoning, treated with plasma exchange from December 2000 to December 2005 were collected and analyzed. Measured laboratory factors, performed before and after plasma exchange treatment included routine biochemistry and hematology tests as well as arsenic concentrations in blood, urine, and discarded plasma. RESULTS: During the study period, 12 patients with severe acute arsine poisoning were treated with plasma exchange. Plasma exchange was performed one or two times on each patient, during which the replacement fluid was fresh frozen plasma (total volume ranged from 1,400 to 4,000 mL). The range of concentrations of arsenic in discarded plasma was 27.7 to 88.7 mg/L and the range of total arsenic removed by plasma exchange was 55.4 to 177.4 mg. Plasma exchange appears to rapidly terminate arsine-induced hemolysis and favorably modify damage to the kidneys and other organs. Laboratory factors that showed significant association with treatment response were creatine kinase, lactate dehydrogenase, blood urea nitrogen, total bilirubin, and heart-related enzymes. All patients recovered from the poisoning and were in good condition at a 2 to 3 months follow-up. CONCLUSIONS: Plasma exchange appears to be an effective treatment intervention for patients with severe acute arsine poisoning. It is suggested that it be used as early as possible.

[Mapping study of ankylosing spondylitis on HLA region in Jilin population of China].

To find the susceptible genes of ankylosing spondylitis in Chinese population, we select 11 SNPs on gene HLA gene family that has strong linkage of ankylosing spondylitis in 6p21.3. By case-control study in 79 AS patients and 132 healthy subjects, the distribution of TNF-alpha-850 genotype TT is higher in AS group than that in normal control group (P=0.027); Mutational allele T has a significant statistically difference between AS group and normal control group (P=0.002). By linkage disequilibrium study, there are 5 SNPs present the linkage disequilibrium and the region is 15 kb, including gene LTA, TNF-alpha, LST1 and NCR3; In the haplotypes of the 5 SNPs , the distribution of haplotype TCTTC has statistical difference between AS group and normal control group (chi2=7.406, P=0.0065), the haplotype contains mutational allele T of TNF-alpha-850. The result hints that there may be susceptible sites of AS in this 15 kb region, which may be TNF-alpha-850 C-->T mutation or other sites that around the TNF-alpha-850.

Polyacrylate/nanosilica causes pleural and pericardial effusion, and pulmonary fibrosis and granuloma in rats similar to those observed in exposed workers.

Nanomaterials offer great benefit as well as potential damage to humans. Workers exposed to polyacrylate coatings have pleural effusion, pericardial effusion, and pulmonary fibrosis and granuloma, which are thought to be related to the high exposure to nanomaterials in the coatings. The study aimed to determine whether polyacrylate/silica nanoparticles cause similar toxicity in rats, as observed in exposed workers. Ninety male Wistar rats were randomly divided into five groups with 18 rats in each group. The groups included the saline control group, another control group of polyacrylate only, and low-, intermediate-, and high-dose groups of polyacrylate/nanosilica with concentrations of 3.125, 6.25, and 12.5 mg/kg. Seventy-five rats for the 1-week study were terminated for scheduled necropsy at 24 hours, 3 days, and 7 days postintratracheal instillation. The remaining 15 rats (three males/group) had repeated ultrasound and chest computed tomography examinations in a 2-week study to observe the pleural and pericardial effusion and pulmonary toxicity. We found that polyacrylate/nanosilica resulted in pleural and pericardial effusions, where nanosilica was isolated and detected. Effusion occurred on day 3 and day 5 post-administration of nanocomposites in the 6.25 and 12.5 mg/kg groups, it gradually rose to a maximum on days 7-10 and then slowly decreased and disappeared on day 14. With an increase in polyacrylate/nanosilica concentrations, pleural effusion increased, as shown by ultrasonographic qualitative observations. Pulmonary fibrosis and granuloma were also observed in the high-dose polyacrylate/nanosilica group. Our study shows that polyacrylate/nanosilica results in specific toxicity presenting as pleural and pericardial effusion, as well as pulmonary fibrosis and granuloma, which are almost identical to results in reported patients. These results indicate the urgent need and importance of nanosafety and awareness of toxicity of polyacrylate/nanosilica.