Identification and characterization of camptothecin tailoring enzymes in Nothapodytes tomentosa.

Camptothecin is a complex monoterpenoid indole alkaloid with remarkable antitumor activity. Given that two C-10 modified camptothecin derivatives, topotecan and irinotecan, have been approved as potent anticancer agents, there is a critical need for methods to access other aromatic ring-functionalized congeners (e.g., C-9, C-10, etc.). However, contemporary methods for chemical oxidation are generally harsh and low-yielding when applied to the camptothecin scaffold, thereby limiting the development of modified derivatives. Reported herein, we have identified four tailoring enzymes responsible for C-9 modifications of camptothecin from Nothapodytes tomentosa, via metabolomic and transcriptomic analysis. These consist of a cytochrome P450 (NtCPT9H) which catalyzes the regioselective oxidation of camptothecin to 9-hydroxycamptothecin, as well as two methyltransferases (NtOMT1/2, converting 9-hydroxycamptothecin to 9-methoxycamptothecin), and a uridine diphosphate-glycosyltransferase (NtUGT5, decorating 9-hydroxycamptothecin to 9-ß-D-glucosyloxycamptothecin). Importantly, the critical residues that contribute to the specific catalytic activity of NtCPT9H have been elucidated through molecular docking and mutagenesis experiments. This work provides a genetic basis for producing camptothecin derivatives through metabolic engineering. This will hasten the discovery of novel C-9 modified camptothecin derivatives, with profound implications for pharmaceutical manufacture.

[Evaluation of Efficacy and Prognosis Analysis of Stage III-IV SMARCA4-deficient 
Non-small Cell Lung Cancer Treated by PD-1 Immune Checkpoint Inhibitors plus 
Chemotherapy and Chemotherapy].

BACKGROUND: The SMARCA4 mutation has been shown to account for at least 10% of non-small cell lung cancer (NSCLC). In the present, conventional radiotherapy and targeted therapy are difficult to improve outcomes due to the highly aggressive and refractory nature of SMARCA4-deficient NSCLC (SMARCA4-DNSCLC) and the absence of sensitive site mutations for targeted drug therapy, and chemotherapy combined with or without immunotherapy is the main treatment. Effective SMARCA4-DNSCLC therapeutic options, however, are still debatable. Our study aimed to investigate the efficacy and prognosis of programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) in combination with chemotherapy and chemotherapy in patients with stage III-IV SMARCA4-DNSCLC. METHODS: 46 patients with stage III-IV SMARCA4-DNSCLC were divided into two groups based on their treatment regimen: the chemotherapy group and the PD-1 ICIs plus chemotherapy group, and their clinical data were retrospectively analyzed. Efficacy assessment and survival analysis were performed in both groups, and the influencing factors for prognosis were explored for patients with SMARCA4-DNSCLC. RESULTS: Male smokers are more likely to develop SMARCA4-DNSCLC. There was no significant difference in the objective response rate (76.5% vs 69.0%, P=0.836) between chemotherapy and the PD-1 ICIs plus chemotherapy or the disease control rate (100.0% vs 89.7%, P=0.286). The one-year overall survival rate in the group with PD-1 ICIs plus chemotherapy was 62.7%, and that of the chemotherapy group was 46.0%. The difference in median progression-free survival (PFS) between the PD-1 ICIs plus chemotherapy group and the chemotherapy group was statistically significant (9.3 mon vs 6.1 mon, P=0.048). The results of Cox regression analysis showed that treatment regimen and smoking history were independent influencing factors of PFS in patients with stage III-IV SMARCA4-DNSCLC, and family history was an individual influencing factor of overall survival in patients with stage III-IV SMARCA4-DNSCLC. CONCLUSIONS: Treatment regimen may be a prognostic factor for patients with SMARCA4-DNSCLC, and patients with PD-1 ICIs plus chemotherapy may have a better prognosis.

Pleural cryptococcosis diagnosed by pleural biopsy in an immunocompromised patient: a case report.

Objective: The aim of this study is to report an isolated pleural cryptococcosis with pleural effusion as the only manifestation, confirmed by pleural biopsy in a patient with thymoma combined with myasthenia gravis, who developed pleural effusion of unknown origin after long-term glucocorticoids and tacrolimus therapy. Methods: Pathological examination of the right pleural biopsy tissue from a patient with unexplained recurrent pleural effusion was implemented. Morphological analysis of the fungal component and metagenomic next-generation sequencing (mNGS) on the pleural tissue were performed. Results: A biopsy specimen of the right pleura revealed numerous yeast-like organisms surrounded by mucous capsules and Cryptococcus neoformans was detected by mNGS with a species-specific read number (SSRN) of 4, confirming the diagnosis of pleural cryptococcosis. Pleural effusion was eliminated with amphotericin B and fluconazole, and healthy status was maintained at the time of review 1 year later. Conclusion: Cryptococcosis, manifested by simple pleural effusion, is extremely rare, but when repeated pleural effusion occurs in immunocompromised patients or in patients with malignant tumors, the possibility of cryptococcosis should be treated with high vigilance and pleural biopsy is recommended if necessary in order to confirm the diagnosis.

Transcriptomic profiling and longitudinal study reveal the relationship of anti-MDA5 titer and type I IFN signature in MDA5+ dermatomyositis.

Objective: This study aimed to investigate the relationship between anti-MDA5 titer and type I IFN signature in patients with MDA5+ DM. Methods: We explored the transcriptome profiling of PBMCs in MDA5+ DM patients with high-titer of antibody at disease onset or relapse and normal low-titer after treatment and healthy donors. Subsequently, we revealed the dynamic relationship between serum type I IFN scores and antibody titers. Result: Differentially expressed genes in MDA5+ DM patients were enriched for related pathways and biological functions linked to viruses and cytokines compared to healthy donors. Similar differences remained pooled between the high-titer and low-titer group, and type I-specific interferon response genes showed upregulation in high-titer group. Significant correlations were found between anti-MDA5 titers and type I IFN scores (r = 0.50, P< 0.001). Contemporaneous anti-MDA5 titers revealed to be significantly higher in the group with ultra-high type I IFN scores (vs. high group, P = 0.027; vs. low group, P< 0.001). Longitudinal assessment of type I IFN scores and anti-MDA5 titers, including pre- and post-treatment changes at initial diagnosis and dynamic changes during treatment, presented an asynchrony between the two parameters in response to treatment. Conclusion: Anti-MDA5 antibody titers correlated with type I IFN signature in patients with MDA5+ DM and they both changed dynamically but not synchronously over the course of treatment.

Diagnostic efficacy of metagenomic next generation sequencing in bronchoalveolar lavage fluid for proven invasive pulmonary aspergillosis.

Objective: To assess the diagnostic efficacy of metagenomic next generation sequencing (mNGS) for proven invasive pulmonary aspergillosis (IPA). Methods: A total of 190 patients including 53 patients who had been diagnosed with proven IPA were retrospectively analyzed. Using the pathological results of tissue biopsy specimens as gold standard, we ploted the receiver operating characteristic (ROC) curve to determine the optimal cut-off value of mNGS species-specific read number (SSRN) of Aspergillus in bronchoalveolar lavage fluid (BALF)for IPA. Furthermore, we evaluated optimal cut-off value of mNGS SSRN in different populations. Results: The optimal cut-off value of Aspergillus mNGS SSRN in BALF for IPA diagnosis was 2.5 for the whole suspected IPA population, and 1 and 4.5 for immunocompromised and diabetic patients, respectively. The accuracy of mNGS was 80.5%, 73.7% and 85.3% for the whole population, immunocompromised and diabetic patients, respectively. Conclusions: The mNGS in BALF has a high diagnostic efficacy for proven IPA, superioring to Aspergillus culture in sputum and BALF and GM test in blood and BALF. However, the cut-off value of SSRN should be adjusted when in different population.

Exosomes derived from bone marrow mesenchymal stem cells inhibit neuroinflammation after traumatic brain injury.

Exosomes derived from bone marrow mesenchymal stem cells can inhibit neuroinflammation through regulating microglial phenotypes and promoting nerve injury repair. However, the underlying molecular mechanism remains unclear. In this study, we investigated the mechanism by which exosomes derived from bone marrow mesenchymal stem cells inhibit neuroinflammation. Our in vitro co-culture experiments showed that bone marrow mesenchymal stem cells and their exosomes promoted the polarization of activated BV2 microglia to their anti-inflammatory phenotype, inhibited the expression of proinflammatory cytokines, and increased the expression of anti-inflammatory cytokines. Our in vivo experiments showed that tail vein injection of exosomes reduced cell apoptosis in cortical tissue of mouse models of traumatic brain injury, inhibited neuroinflammation, and promoted the transformation of microglia to the anti-inflammatory phenotype. We screened some microRNAs related to neuroinflammation using microRNA sequencing and found that microRNA-181b seemed to be actively involved in the process. Finally, we regulated the expression of miR181b in the brain tissue of mouse models of traumatic brain injury using lentiviral transfection. We found that miR181b overexpression effectively reduced apoptosis and neuroinflamatory response after traumatic brain injury and promoted the transformation of microglia to the anti-inflammatory phenotype. The interleukin 10/STAT3 pathway was activated during this process. These findings suggest that the inhibitory effects of exosomes derived from bone marrow mesenchymal stem cells on neuroinflamation after traumatic brain injury may be realized by the action of miR181b on the interleukin 10/STAT3 pathway.

Comparative effectiveness of non-pharmacological interventions for preventing delirium in critically ill adults: A systematic review and network meta-analysis.

BACKGROUND: Delirium presents a serious health problem in critically ill patients in intensive care units. However, knowledge regarding the selections of the optimal non-pharmacological interventions remains unclear. OBJECTIVES: To compare the effects of non-pharmacological interventions by combining direct and indirect evidence on the incidence and duration of delirium in intensive care units. DESIGN: A systematic review and network meta-analysis. DATA SOURCES: A comprehensive search of five electronic databases, including PubMed, EMBASE, CINAHL, Cochrane CENTRAL, and ProQuest Dissertations and Theses A&I were conducted. Only randomized control trials published from the inception to December 28, 2021 were included. REVIEW METHODS: Two reviewers independently screened the title and abstract for eligibility according to the inclusion and exclusion criteria. The random-effect network meta-analysis was used to estimate the comparative effects of non-pharmacological interventions in reducing delirium incidence and duration. RESULTS: A total of 29 studies with 7005 critically ill patients were enrolled. Twenty-six and eleven studies reported the delirium incidence and duration, respectively. Component-based intervention comparison revealed that multicomponent strategy was the most effective non-pharmacological intervention compared to usual care in reducing incidence of ICU delirium (Odd ratio [OR]=0.43, 95% CI= 0.22-0.84) but not ICU delirium duration. Treatment-based intervention comparisons indicated that specific multi-treatment interventions significantly reduced the ICU delirium incidence and duration, particularly the involvement of early mobilization and family participation (OR = 0.12 with 95% CI = 0.02 to 0.83; mean difference = -1.34 with 95% CI = -2.52 to -0.16, respectively). CONCLUSION: Our study suggests that the multicomponent strategy was the most effective non-pharmacological intervention in reducing the incidence of ICU delirium. Early mobilization and family participation involvement in non-pharmacological interventions seemed to be more effective in reducing the incidence of ICU delirium. These results of network-meta analysis could be an important evidence-based for clinical healthcare providers to optimize the critical care protocol. TWEETABLE ABSTRACT: Network meta-analysis of 29 randomised controlled trials with 7005 patients finds that multicomponent interventions, particularly those involving early mobilization, family participation, cognitive stimulation, reorientation, sensory stimulation, environment control and clinical adjustment, is the most effective non-pharmacological strategy to reduce the incidence of delirium in intensive care units.

Comparative efficacy of nonpharmacological interventions on sleep quality in people who are critically ill: A systematic review and network meta-analysis.

BACKGROUND: Disrupted sleep is a critical and highly prevalent concern among critically ill patients requiring intensive care. However, the question of which nonpharmacological intervention represents the best strategy for improving sleep quality remains unanswered. OBJECTIVE: To compare the efficacy of nonpharmacological interventions in improving sleep quality in people who are critically ill. METHODS: Databases, namely PubMed, Embase, CINAHL, and ProQuest Dissertations and Theses A&I, were searched from their inception up until January 15, 2021, for relevant randomised controlled trials. No language or time period restrictions were applied. Only randomised controlled trials examining the effects of nonpharmacological interventions on sleep among adults (aged ≥18 years) admitted to an intensive care unit were included. A random-effects model was used for data analyses. The study protocol was registered at PROSPERO (CRD42021232004). RESULTS: Twenty randomised controlled trials involving 1,207 participants were included. Music combined with earplugs and eye masks (standardised mean difference =1.64), eye masks alone (0.98), aromatherapy (0.87), and earplugs combined with eye masks (0.61) significantly improved sleep quality compared with routine care (all p <0.05). Music combined with earplugs and eye masks significantly enhanced sleep quality in comparison with music (1.34), earplugs combined with eye masks (1.03), and nursing intervention (1.76, all p <0.05). Earplugs alone was less likely to have effects on sleep quality improvement compared with routine care. CONCLUSION: Eye masks alone and music combined with earplugs and eye masks appear to be the most effective interventions for improving sleep quality in people who are critically ill. Critical care nurses should incorporate the use of eye masks alone or music combined with eye masks into sleep care.

Comparison of 1.0 g/kg of 20% mannitol initiated at different time points and effects on brain relaxation in patients with midline shift undergoing supratentorial tumor resection: a randomized controlled trial.

OBJECTIVE: Previous studies have suggested the use of 1.0 g/kg of 20% mannitol at the time of skin incision during neurosurgery in order to improve brain relaxation. However, the incidence of brain swelling upon dural opening is still high with this dose. In the present study, the authors sought to determine a better timing for mannitol infusion. METHODS: One hundred patients with midline shift who were undergoing elective supratentorial tumor resection were randomly assigned to receive early (immediately after anesthesia induction) or routine (at the time of skin incision) administration of 1.0 g/kg body weight of 20% mannitol. The primary outcome was the 4-point brain relaxation score (BRS) immediately after dural opening (1, perfectly relaxed; 2, satisfactorily relaxed; 3, firm brain; and 4, bulging brain). The secondary outcomes included subdural intracranial pressure (ICP) measured immediately before dural opening; serum osmolality and osmole gap (OG) measured immediately before mannitol infusion (T0) and at the time of dural opening (TD); changes in serum electrolytes, lactate, and hemodynamic parameters at T0 and 30, 60, 90, and 120 minutes thereafter; and fluid balance at TD. RESULTS: The time from the start of mannitol administration to dural opening was significantly longer in the early administration group than in the routine administration group (median 66 [IQR 55-75] vs 40 [IQR 38-45] minutes, p < 0.001). The BRS (score 1/2/3/4, n = 14/26/9/1 vs 3/25/18/4, p = 0.001) was better and the subdural ICP (median 5 [IQR 3-6] vs 7 [IQR 5-10] mm Hg, p < 0.001) was significantly lower in the early administration group than in the routine administration group. Serum osmolality and OG increased significantly at TD compared to levels at T0 in both groups (all p < 0.001). Intergroup comparison showed that serum osmolality and OG at TD were significantly higher in the routine administration group (p < 0.001 and = 0.002, respectively). Patients who had received early administration of mannitol had more urine output (p = 0.001) and less positive fluid balance (p < 0.001) at TD. Hemodynamic parameters, serum lactate concentrations, and incidences of electrolyte disturbances were comparable between the two groups. CONCLUSIONS: Prolonging the time interval between the start of mannitol infusion and dural incision from approximately 40 to 66 minutes can improve brain relaxation and decrease subdural ICP in elective supratentorial tumor resection.

Effect of strict intraoperative blood pressure management strategy on postoperative acute kidney injury in non-cardiac surgery: A meta-analysis of randomised controlled trials.

BACKGROUND: Acute kidney injury (AKI) is one of the most serious perioperative complications. 20% to 40% of high-risk patients who undergo non-cardiac surgery have AKI and those with AKI are eight-times more likely to die within 30 days after surgery. It may be related to intraoperative hypotension, which is mainly caused by vasodilatory and cardiodepressant effects of anaesthesia, and/or hypovolemia. Strict intraoperative blood pressure management strategy (strict BP management) is a potential option to prevent postoperative AKI. This strategy refers to additional administration of vasoactive agents under the premise of a protocolised fluid delivery. The efficacy of strict BP management for preventing postoperative AKI in non-cardiac surgery patients was assessed by a meta-analysis. METHODS: We systematically retrieved randomised controlled trials (RCTs) and compared strict BP management with conventional therapy control on effect of postoperative AKI in non-cardiac surgery patients, which were published on PubMed, EMBASE, Cochrane library and Web of Science databases before October 5, 2020. Ultimately, a meta-analysis of all RCTs eligible for inclusion criteria was performed. RESULTS: Five RCTs, comprising 1485 patients, were included in the meta-analysis. Strict BP management was associated with a reduced incidence of postoperative AKI [relative risk (RR) = 0.73, 95% confidence interval (CI): 0.58-0.92, P = .007]. No significant difference was found between strict BP management group and conventional therapy control in mortality at longest follow-up available (RR = 0.92, 95% CI: 0.68-1.25, P = .60). In the subset analysis, the studies using supranormal BP management target was significantly lower in the incidence of postoperative AKI (RR = 0.65, 95% CI: 0.51-0.82, P = .0003) CONCLUSION: Strict BP management is significantly more effective than conventional therapy for the prevention of postoperative AKI. Supranormal target of intraoperative BP management may be considered a more appealing option for the prevention of AKI.

Intravitreal dexamethasone implant - a new treatment for idiopathic posterior scleritis: A case report.

BACKGROUND: Posterior scleritis is one of the most easily missed and misdiagnosed diseases in ophthalmology. In this case we treated a patient with intravitreal dexamethasone implant that has not been extensively studied before. CASE SUMMARY: A 40-year-old female patient who had anxiety, palpitation, and insomnia presented with eye pain and decreased vision in the left eye. An eye examination indicated that her visual acuity (VA) was 40/100. Her left eye presented conjunctival edema, mild exophthalmos, clear cornea, KP(-), and clear aqueous humor. In the fundus, there was a cinerous retinal protuberance. Ultrasonography showed "T-sign" and no systemic association was detected in laboratory examination. One month after injection of dexamethasone implant, the patient exhibited VA of 20/20, fundus serous retinal detachment disappeared, and intraocular pressure of both eyes was at the normal level. CONCLUSION: Intravitreal injection of dexamethasone implant may be a safe and effective treatment for patients with idiopathic posterior scleritis.

Comparing two airway management strategies for moderately sedated patients undergoing awake craniotomy: A single-blinded randomized controlled trial.

BACKGROUND: In the monitored anesthesia care (MAC) setting for awake craniotomy (AC), maintaining airway patency in sedated patients remains challenging. This randomized controlled trial aimed to compare the validity of the below-epiglottis transnasal tube insertion (the tip of the tube placed between the epiglottis and vocal cords) and the nasopharyngeal airway (simulated by the above-epiglottis transnasal tube with the tip of the tube placed between the epiglottis and the free edge of the soft palate) with respect to maintaining upper airway patency for moderately sedated patients undergoing AC. METHODS: Sixty patients scheduled for elective AC were randomized to receive below-epiglottis (n = 30) or above-epiglottis (n = 30) transnasal tube insertion before surgery. Moderate sedation was maintained in the pre- and post-awake phases. The primary outcome was the upper airway obstruction (UAO) remission rate (relieved obstructions after tube insertion/the total number of obstructions before tube insertion). RESULTS: The UAO remission rate was higher in the below-epiglottis group [100% (12/12) vs 45% (5/11); P = .005]. The tidal volume values monitored through the tube were greater in the below-epiglottis group during the pre-awake phase (P < .001). End-tidal carbon dioxide (EtCO2 ) monitored through the tube was higher in the below-epiglottis group at bone flap removal (P < .001). During the awake phase, patients' ability to speak was not impeded. No patient had serious complications related to the tube. CONCLUSION: The below-epiglottis tube insertion is a more effective method to maintain upper airway patency than the nasopharyngeal airway for moderately sedated patients undergoing AC.

The Prognostic Value of Preoperative Geriatric Nutritional Risk Index in Patients with Pancreatic Ductal Adenocarcinoma.

PURPOSE: Patients with malignancy are more likely to develop nutritional problems. The Geriatric Nutritional Risk Index (GNRI) is a new prognostic index for evaluating nutritional status. The objective of this study was to assess if preoperative GNRI could be a prognostic factor for patients with pancreatic ductal adenocarcinoma (PDAC) who underwent radical surgery. PATIENTS AND METHODS: This study included 282 consecutive patients with incident pancreatic ductal adenocarcinoma who were treated with radical surgery. The Cox regression analysis was performed to calculate the overall survival (OS) and assess the prognostic factors. A nomogram was developed based on the results of the multivariate analysis, and the predictive accuracy of the nomogram was assessed. RESULTS: Among the 282 patients, there are 117 males and 165 females. The patients had a mean age of 58.7 ±13.5 years, with the median follow-up time of 72.9 months (interquartile range, 0.7 to 115.2 months). They were classified into abnormal (GNRI ≤ 98) and normal (GNRI > 98) GNRI groups, respectively. Multivariate Cox analysis showed that age (HR = 1.023), drinking history (HR = 1.453), tumor grade (HR = 1.633), TNM stage (HR = 1.921), and GNRI (HR = 1.757) were significantly associated with OS. Based on the above variables, the nomogram was established. The concordance index (C-index) and time-dependent receiver operating characteristics curve (tdROC) showed the nomogram was superior to TNM grade and tumor grade in predicting the OS of patients with PDAC. CONCLUSION: GNRI could be a useful prognostic indicator in patients with PDAC who received surgery. Based on the GNRI and the other clinical indicators, we developed a nomogram model that can provide an accurate estimation of OS in patients with PDAC after radical surgery.

Age estimation by multidetector computed tomography of cranial sutures in Chinese male adults.

OBJECTIVES: This study aimed to explore whether computed tomography (CT) images of cranial sutures can contribute to adult age estimation in Chinese Han individuals. MATERIALS AND METHODS: This study was based on cranial CT scans of 230 Chinese Han males aged 23.33-76.93 years. A total of 160 images from 16 suture segments were scored after volume reformation and multiplanar reconstruction in each individual. Decision tree regression, linear support vector regression, Bayesian ridge regression, and gradient boosting regression were developed for adult age estimation by a training set using leave-one-out cross-validation and further evaluated by the test set. The inaccuracy and bias were calculated to evaluate the four models and the previously used models from the literature. RESULTS: The degree of suture closure was associated with adult age. The minimum inaccuracy of the test set was 7.73 years obtained by linear support vector regression, while the inaccuracy of previous simple linear regression models was 13.09 and 10.97 years. The accuracy was higher in the age group from 40.00 to 59.99 years compared to the other age groups. DISCUSSION: The accuracy of our models for adult age estimation was superior to those in previous studies based on cranial sutures. Hence, the application of novel statistical data mining tools helps to improve aging issues. Nevertheless, age estimation of adults should be combined with other methods, since the accuracy level is still not satisfactory.

Differential circRNA expression profiles in latent human cytomegalovirus infection and validation using clinical samples.

Human cytomegalovirus (HCMV) is an opportunistic prototypic beta-herpesvirus that can cause severe and even fatal diseases in immune-naive newborns and immunocompromised adults. Host-virus interactions occurring at the transcriptional and posttranscriptional levels are critical for establishing an HCMV latent or lytic infection, but the mechanisms remain poorly understood. Herein, we investigated the expression of circRNAs in human leukemia monocytes (THP-1 cells) latently infected with HCMV and explored the diagnostic value of circRNAs in children with HCMV infection. A total of 2,110 and 1,912 circRNAs were identified in mock-infected and HCMV latent-infected THP-1 cells, respectively. Of these, we identified 1,421 differently expressed circRNAs, of which 650 were upregulated and 771 were downregulated. The host genes corresponding to the differentially expressed circRNAs were mainly involved in the regulation of host cell secretion pathways, cell cycle, and cell apoptosis. The differentially expressed circRNAs had binding sites for microRNAs, suggesting an important role in the mechanism of HCMV latent infection. Furthermore, a clinical analysis showed that the expression levels of hsa_circ_0001445 and hsa_circ_0001206 were statistically significantly different in HCMV-infected patients vs. normal controls, suggesting that these circRNAs could potentially serve as biomarkers of HCMV-infection.

Fucoidan Alleviates Acetaminophen-Induced Hepatotoxicity via Oxidative Stress Inhibition and Nrf2 Translocation.

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that leads to severe hepatotoxicity at excessive doses. Fucoidan, a sulfated polysaccharide derived from brown seaweeds, possesses a wide range of pharmacological properties. However, the impacts of fucoidan on APAP-induced liver injury have not been sufficiently addressed. In the present study, male Institute of Cancer Research (ICR) mice aged 6 weeks were subjected to a single APAP (500 mg/kg) intraperitoneal injection after 7 days of fucoidan (100 or 200 mg/kg/day) or bicyclol intragastric administration. The mice continued to be administered fucoidan or bicyclol once per day, and were sacrificed at an indicated time. The indexes evaluated included liver pathological changes, levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum, levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT) in the liver, and related proteins levels (CYP2E1, pJNK and Bax). Furthermore, human hepatocyte HL-7702 cell line was used to elucidate the potential molecular mechanism of fucoidan. The mitochondrial membrane potential (MMP) and nuclear factor-erythroid 2-related factor (Nrf2) translocation in HL-7702 cells were determined. The results showed that fucoidan pretreatment reduced the levels of ALT, AST, ROS, and MDA, while it enhanced the levels of GSH, SOD, and CAT activities. Additionally, oxidative stress-induced phosphorylated c-Jun N-terminal protein kinase (JNK) and decreased MMP were attenuated by fucoidan. Although the nuclear Nrf2 was induced after APAP incubation, fucoidan further enhanced Nrf2 in cell nuclei and total expression of Nrf2. These results indicated that fucoidan ameliorated APAP hepatotoxicity, and the mechanism might be related to Nrf2-mediated oxidative stress.

The role of multislice computed tomography of the costal cartilage in adult age estimation.

To establish population-specific age estimation models in adults from costal cartilage for contemporary Chinese by using three-dimensional volume-rendering technique. Five hundred and twelve individuals (254 females and 258 males) with documented ages between 20 and 85 years were retrospectively included. Their clinical CT examinations (1 mm slice thickness) were used to develop the sex-specific age prediction model. A validation sample comprising 26 female and 24 male individuals was then used to test the predictive accuracy of the established models. Simple linear regression (SLR), multiple linear regression (MLR), gradient boosting regression (GBR), support vector machine (SVM), and decision tree regression (DTR) were utilized to build the age diagnosis models from calibration samples. By comparison, the decision tree regression was the relatively more accurate age prediction model for male, with mean absolute error = 5.31 years, least absolute error = 0.10 years, correct percentage within 5 years = 54%, and the correct percentage within 10 years = 88%. The stepwise multiple linear regression equations was the relatively more accurate one for female, with mean absolute error = 6.72 years, least absolute error = 0.68 years, correct percentage within 5 years = 42%, and correct percentage within 10 years = 77%. Our results indicated that the present established age estimation model can be applied as an additional guidance for age estimation in adults.

Antidepressant-like effects of ginsenoside Rg2 in a chronic mild stress model of depression.

Major depression is a common neuropsychiatric disease with high lifetime prevalence and high incidence of suicide. This study aimed to evaluate the antidepressant effects of ginsenoside Rg2 in mice, and the possible mechanism was also determined. A single injection of both Rg2 (10 and 20mg/kg) and fluoxetine (positive control, 20mg/kg) induced notable antidepressant-like effects in the forced swim test and tail suspension test without affecting the locomotor activity of mice, and the tests were done 30min after the injection. Also, repeated daily treatment of Rg2 and fluoxetine for the last 2 weeks fully reversed the chronic mild stress (6 weeks)-induced depressive-like symptoms in mice. Moreover, western blot analysis showed that Rg2 administration significantly increased the BDNF signaling pathway in hippocampus. Importantly, the usage of TrkB shRNA fully blocked the antidepressant effects of Rg2 in mice. Collectively, these results suggest that Rg2 produces an antidepressant-like effect in mice which is mediated, at least in part, through promoting the hippocampal BDNF signaling pathway.

Investigation of pathology malpractice claims in China from 2002-2015.

OBJECTIVE: To examine pathology-related medical claims in China and identify the most common errors to result in such claims. METHOD: A retrospective analysis was performed of 71 forensic evaluation reports carried out in two Chinese institutes of forensic medicine between 2002 and 2015 due to suspicion of medical malpractice. The judicial outcomes of each case were also reviewed when available. RESULTS: Of 71 cases, 54 cases had judicial outcomes. The most frequently claimed events were false-negative diagnoses of skin cancer, invasive ductal carcinoma of the breast, and osteosarcoma; and false positive diagnoses of uterine cervical squamous cell carcinoma, gastric carcinoma, and soft tissue carcinoma. The most common cause of error (82%, 56 of 68) was pathological misinterpretation. Plaintiffs in most cases (89%, 48 of 54) received compensation. CONCLUSION: Our data are in agreement with other findings regarding the most frequent medical malpractice allegations related to pathology. Addressing the issues at the root of these claims would lead to a decline in the number of medical errors. Quality assurance programs and good pathologist-clinician communication may decrease the risk of litigation.

Long-term outcomes of ciliary sulcus versus capsular bag fixation of intraocular lenses in children: An ultrasound biomicroscopy study.

PURPOSE: To evaluate the long-term outcomes of ciliary sulcus versus capsular bag fixation of intraocular lenses (IOLs) in children after pediatric cataract surgery. METHODS: IOL was implanted in the ciliary sulcus in 21 eyes of 14 children, and in the capsular bag in 19 eyes of 12 children for the treatment of pediatric cataract in an institutional setting. Ultrasound biomicroscopy (UBM) was performed. Main outcome measures included IOL decentration, IOL tilt, anterior chamber depth (ACD), angle-opening distance at 500 µm (AOD500), trabecular-iris angle (TIA), best-corrected visual acuity (BCVA), intraocular pressure (IOP), and incidence of postoperative complications. RESULTS: The mean follow-up period was 6.81 ± 1.82 years. Comparing to the capsular bag fixation group, the ciliary sulcus fixation group had higher vertical IOL decentration, horizontal IOL tilt, and vertical IOL tilt (p = 0.02, 0.01,0.01, respectively), higher incidence of iris-IOL contact and peripheral anterior synechia (p = 0.001, 0.03, respectively), smaller ACD, AOD500, and TIA (p = 0.02, 0.03, 0.04, respectively), higher mean IOP (17.10 ±6.06 mmHg vs.14.15± 4.74 mmHg, p = 0.01), and higher incidence of secondary glaucoma (28.57% vs. 10.53%, p = 0.007).There was no significant difference between the two groups with regard to the BCVA, refractive errors, incidence of myopic shift, nystagmus, strabismus, and visual axis opacity. CONCLUSIONS: Ciliary sulcus fixation of IOLs in pediatric eyes may increase IOL malposition and crowding of the anterior segment, and may associate with a higher risk of secondary glaucoma compared to capsular bag fixation of IOLs.